ISSUES AND CONTROVERSIES IN PRIMARY PTCA

Issues and Controversies in Primary PTCA


DrG.KrishnaKanth


Various issues involved which can make difference between Primary and conventional PTCA :

1)Primary PTCA vs Thrombolytic therapy 2)Antiplatelet regimen to be given 3)Access Site 4)Anticoagulation 4)Gp IIb-IIIa blocker 5)Thrombosuction 6)Methods to improve Microvascular Perfusion 7)Tackling Multivessel CAD in Primary PTCA 8)LMCA in primary PTCA. 9)DES vs BMS in Primary PTCA.








www.escardio.org/guidelines



INDICATIONS FOR PRIMARY PCI/ CAG




Primary PCI is preferred to fibrinolytic therapy when Time-to-treatment delays are short and The patient presents to a high-volume, well-equipped center

staffed with expert interventional cardiologists and skilled support staff. Compared with fibrinolytic therapy in RCTs, primary PCI

produces: Higher rates for infarct artery patency, TIMI flow grade 3, and Lower rates for recurrent ischemia, Reinfarction, Emergency repeat revascularization procedures, Intracranial hemorrhage, and Death . Early, successful PCI also greatly decreases the complications of STEMI that result from longer ischemic times or unsuccessful

fibrinolytic therapy, allowing earlier hospital discharge and resumption of daily activities.



ESC indications of Primary PCI



www.escardio.org/guidelines


Antiplatelet therapyIssue of Clopidogrel Resistance & How to overcome it??? Non-responsiveness to clopidogrel may be observed in up to

30% of patients, and it is associated with a worse prognosis after coronary stenting. This issue may be of high clinical relevance particularly in

patients receiving drug-eluting stents, due to higher risk of late in-stent thrombosis.

Due to the impact of SAT on mortality after primary angioplasty, non-responsiveness to clopidogrel would deserve larger attention.

Future randomized trials are certainly needed to identify the optimal strategy to be adopted among these patients, including higher daily dose (150 mg), switch to ticlopidine60 or new ADP antagonist, or adjunctive oral anticoagulation therapy.



The PLATO trial (ticagrelor plus aspirin compared with clopidogrel plus aspirin) and TRITON-TIMI 38, which compared prasugrel plus aspirin with clopidogrel plus aspirin in patients (n = 13,608) with ACS and scheduled PCI.

The PLATO and TRITON-TIMI 38 trials were similar in many ways, both including populations with ACS, both comparing the intervention plus aspirin to clopidogrel plus aspirin, and both sharing the same primary end point.

There were important differences in the use of PCI and medical management, in the size and timing of the loading dose of clopidogrel, and in assessing myocardial infarction.

ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update

26

TRITON-TIMI 38:Study Design

Double-blind

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 Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Wiviott SD et al AHJ 152: 627,2006Adapted with permission from E.Antman


27

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

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167Adapted with permission from Wiviott SD et al NEJM 357:2007

TRITON: Results


28

B

OVERALL

No GPIGPI

DESBMS

DMNo DM

>7565-74

<65

FemaleMale

STEMIUA/NSTEMI

0.5 1 2Prasugrel Better Clopidogrel Better

HR

Age

Reduction in risk (%)18

2112

25146

1430

2018

2116

19

21

Pinter = NS

CV Death, MI, StrokeCV Death, MI, StrokeMajor SubgroupsMajor Subgroups

CrCl > 60CrCl < 60 14

20

Wiviott SD et al NEJM 357: 2001, 2007

TRITON TIMI-38


31

0

5

10

15

0 30 60 90 180 270 360 450

Per

cen

t (%

)

Days From Randomization

9.5%

6.5%

HR 0.68(0.54-0.87)

P=0.002

12.4%

10.0%

HR 0.79(0.65-0.97)

P=0.02

Clopidogrel

Prasugrel

NNT = 42

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

Clopidogrel

Prasugrel 2.4

2.1

STEMI CohortSTEMI CohortN=3534N=3534

Montalescot et al Lancet 2008.Adapted with permission from Antman EM.

TRITON TIMI-38


32

Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

En

dp

oin

t (%

)

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

Adapted with permission from Wiviott SD et al Lancet 2008

Significant reductions both with BMS, DESSignificant reductions both with BMS, DESSignificant reductions in early and late stent thrombosesSignificant reductions in early and late stent thromboses

TRITON TIMI-38


34

Recommendations for the use of

Thienopyridines


35

Loading doses for Thienopyridines in Patients with Acute

Coronary Syndromes (STEMI and UA/NSTEMI)


36

Recommendations for the use of Thienopyridines

A loading dose of thienopyridine is recommended for

STEMI patients for whom PCI is planned. Regimens

should be one of the following:

MODIFIED Recommendation

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIIIClopidogrel at least 300 mg to 600mg† should be given as early as possible before or at the time of primary or non-primary PCI.


37

• The optimal loading dose of clopidogrel has not been established

• Randomized clinical trials using >300mg of clopidogrel as a loading dose for PCI in STEMI or UA/NSTEMI have not rigorously established superior safety or efficacy

• Clopidogrel is a prodrug which must undergo hepatic conversion to its active metabolite for platelet inhibition, a process taking several hours.



38


Prasugrel 60 mg should be given

as soon as possible for primary

PCI.


III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII


39

The duration of Thienopyridine therapy


40

Thienopyridines

The duration of thienopyridine therapy

should be as follows: MODIFIED

Recommendation


III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII a. In patients receiving a stent (BMS or DES) during PCI for ACS, clopidogrel 75 mg daily† or prasugrel 10 mg§ daily should be givenfor at least 12 months;

b. If the risk of morbidity from bleeding outweighs the anticipated benefit affordedby thienopyridine therapy, earlier discontinuation should be considered.


41

Thienopyridines


Continuation of clopidogrel orprasugrel beyond 15 months

maybe considered in patientsundergoing drug-eluting stentplacement



42

Thienopyridines

NEW Recommendation

In STEMI patients with a priorhistory of stroke and

transientischemic attack for whom

primaryPCI is planned, prasugrel is

notrecommended as part of a

dualantiplatelet therapy regimen



43


For STEMI patients undergoing non-primary PCI, the

following regimens are recommended:

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII a. …and has been given clopidogrel, it should be continued as the thienopyridine of choice.

b. …without a thienopyridine, a loading dose of 300-600‡ mg of clopidogrel should be given as the thienopyridine of choice.

If the patient did not receive fibrinolytic therapy…c. …either a loading dose of 300-600 mg of clopidogrel

should be given or, once the coronary anatomy is known and PCI is planned, a loading dose of 60 mg of prasugrel should be given promptly and no later than 1 hour after the PCI.


If the patient has received fibrinolytic therapy…

MODIFIED

Rec


44

Thienopyridines


In patients taking a thienopyridine in whom coronaryartery bypass surgery (CABG) is planned and can be delayed, it is recommended that the drug be discontinuedto allow for dissipation of the antiplatelet effect.

The period of withdrawal should be at least 5 days inpatients receiving clopidogrel

and at least 7 days in patients receiving prasugrel,

… unless the need for revascularization and/or the netbenefit of the thienopyridine outweighs the potential risksof excess bleeding.

MODIFIED

Recommendation (prasugrel added)





Access Site

Results of the STEMI-RADIAL trial presented at TCT 2012

MIAMI, OCTOBER 26, 2012 – A study found several benefits in using the radial artery in the arm as the entry point for angioplasty or percutaneous coronary intervention (PCI) compared to the femoral artery in the leg.

Results of the STEMI-RADIAL trial were presented at the 24th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium. (Sponsored by the Cardiovascular Research Foundation CRF)


In the STEMI-RADIAL trial, investigators examined the net clinical benefit of using the radial versus femoral approach in patients presenting within 12 hours of symptom onset of acute ST-elevation myocardial infarction (STEMI).

All investigators were high-volume (>200 PCI/year) operators with significant experience in the radial approach (>80% cases/year)

STEMI-RADIAL was a randomized, national, multicenter, parallel group trial conducted in 707 patients at four high-volume centers.

Patients eligible for both access sites without cardiogenic shock were randomized to the radial or femoral access approach.


The primary endpoint was the cumulative incidence of major bleeding and vascular access site complications (requiring intervention) at 30 days.

Secondary endpoints included major adverse cardiovascular events (MACE: death, reinfarction and stroke), technical success, access site failure, procedural and fluoroscopy times, contrast volume, intensive care stay and target lesion

revascularization.

STEMI-RADIAL

A Prospective Randomized Trial of Radial vs. Femoral Access in Patients with ST-Segment

Elevation Myocardial Infarction

I Bernat, D Horak, J Stasek, M Mates, P Ostadal, J Pesek, V Hrabos, J Dusek, J Koza,

Z Sembera, M Brtko, O Aschermann, M Smid, P Polansky, AA Mawiri, J Bis, J Vojacek,

O Costerousse, OF Bertrand, R Rokyta

University Hospital and Faculty of Medicine Pilsen, Regional Hospital Liberec, University Hospital

Hradec Kralove, Na Homolce Hospital Prague, Université Laval Quebec. Czech Republic, Canada

(ClinicalTrials.gov. NCT 00136187)

STEMI RADIAL - Study design:

707 STEMI patients between October 2009 and February 2012 in 4 PCI centers (24/7)

electronic randomization to femoral or radial approach (www.fnplzen.cz/radial)

femoral approach(n=359)

radial approach(n=348)

Clinical follow-up at 30 days

(100%)

written inform consent in the cathlab

Intention to treat

immediate CAG + pPCI

STEMI RADIAL - results30-day bleeding and access site compl.

p = 0.7

30-day MACE

STEMI RADIAL - results

p = 0.64

p = 0.72

p = 1.0

4.2%

3.5%3.1%

2.3%

0.8%1.2%

0.3% 0.3%

MACE = composite of death, myocardial infarction and stroke

DefinitionsDefinitions

Major Bleeding (CURRENT/OASIS 7)

• Fatal

• > 2 units of Blood transfusion

• Hypotension requiring inotropes

• Leading to hemoglobin drop of ≥ 5 g/dl

• Requiring surgical intervention

• ICH or Intraocular bleeding leading to significant vision loss

Major Vascular Access Site Complications

• Large hematoma

• Pseudoaneurysm requiring closure

• AV fistula

• Other vascular surgery related to the access site

• In patients with STEMI <12 hrs, radial approach was associated with a significant lower incidence of major bleeding and access site complications and a significant better net clinical benefit.

• Moreover radial approach reduced significantly ICU stay and contrast volume compared to femoral approach.

• The results support the use of radial approach in primary PCI in experienced radial centers as a first choice.

Prior Meta-analysis of 23 RCTs of Radial vs. Femoral (N=7030)

Radial better Femoral better1.0

PCI Procedure Failure

Death

Death, MI or stroke

Major bleeding

1.31 (0.87-1.96)

0.74 (0.42-1.30)

0.71 (0.49-1.01)

0.27 (0.16-0.45)

Jolly SS, et al. Am Heart J 2009;157:132-40.

R I V A L

Primary and Secondary OutcomesPrimary and Secondary Outcomes

RadialRadial(n=3507)(n=3507)

%%

Femoral Femoral (n=3514)(n=3514)

%%HRHR 95% CI95% CI PP

Primary Outcome

Death, MI, Stroke, Death, MI, Stroke, Non-CABG Major Non-CABG Major BleedBleed

3.7 4.0 0.92 0.72-1.17 0.50

Secondary Outcomes

Death, MI, Stroke 3.2 3.2 0.98 0.77-1.28 0.90Non-CABG Major Bleeding 0.7 0.9 0.73 0.43-1.23 0.23

R I V A L

Other OutcomesOther Outcomes


%%

FemoralFemoral (n=3514)(n=3514)


Major Vascular Access Site Complications

1.4 3.7 0.37 0.27-0.52<0.000

1

Other Definitions of Major Bleeding

TIMI Non-CABG Major Bleeding

0.5 0.5 1.00 0.53-1.89 1.00

ACUITY Non-CABG Major Bleeding*

1.9 4.5 0.43 0.32-0.57<0.000

1

* Post Hoc analysis

R I V A L

Other OutcomesOther Outcomes


%%



Death 1.3 1.5 0.86 0.58-1.29 0.47

MI 1.7 1.9 0.92 0.65-1.31 0.65

Stroke 0.6 0.4 1.43 0.72-2.83 0.30

Stent Thrombosis 0.7 1.2 0.63 0.34-1.17 0.14

R I V A L

Other Outcomes Other Outcomes



P P

Access site Cross-over (%) 7.6 2.0 <0.0001

PCI Procedure duration (min) 35 34 0.62

Fluoroscopy time (min) 9.3 8.0 <0.0001

Persistent pain at access site >2 weeks (%) 2.6 3.1 0.22

Patient prefers assigned access site for next procedure (%)

90 49 <0.0001

• Symptomatic radial occlusion requiring medical attention 0.2% in radial group

R I V A L

ConclusionConclusion No significant difference between radial and femoral No significant difference between radial and femoral

access in primary outcome of death, MI, stroke or non-access in primary outcome of death, MI, stroke or non-CABG major bleedingCABG major bleeding

Rates of primary outcome appeared to be lower with Rates of primary outcome appeared to be lower with radial compared to femoral access in high volume radial radial compared to femoral access in high volume radial centres and STEMIcentres and STEMI

Radial had fewer major vascular complications with Radial had fewer major vascular complications with similar PCI success similar PCI success


Anticoagulation The goals of pharmacotherapy during PCI are 2-fold:

(1) to mitigate the sequelae of iatrogenic plaque rupture from balloon angioplasty or stenting and

(2) to reduce the risk of thrombus formation on intravascular PCI equipment. Central to these thrombotic events is thrombin (factor IIa).

Iatrogenic damage to the endothelium during PCI leads to increased expression of tissue factor, activation of the coagulation cascade, and formation of activated factor Xa.

This ultimately leads to the generation of thrombin, conversion of fibrinogen to fibrin, and thrombus formation.

In addition to its effects on fibrin, thrombin also directly activates platelets, enhances platelet aggregation, and is proinflammatory.


Aims of optimal antithrombotic therapy.

De Luca G Eur Heart J Suppl 2008;10:J2-J14

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: [email protected]


Because of its multiple actions in promoting thrombosis, the focus of most anticoagulant agents is thrombin inhibition.

Available agents for use include unfractionated heparin (UFH), low-molecular-weight heparins (LMWH, of which enoxaparin has the largest body of clinical data), the synthetic pentasaccharides (of which fondaparinux has the largest body of clinical data), and the direct thrombin inhibitors (DTIs, of which bivalirudin has the largest body of clinical data)




Direct thrombin inhibitors Bivalirudin is a 20-amino acid synthetic polypeptide

analog of hirudin. Once bound, bivalirudin is cleaved by thrombin,

thereby reducing its antithrombotic activity. Peak bivalirudin concentrations are achieved 15–20

min after intravenous infusion. In patients with normal renal function, the plasma

half-life of bivalirudin is 25–36 min. Although it is predominantly eliminated by plasma

enzymes (peptidases), approximately 20% of the drug is excreted via the kidneys.

Unfortunately, there is no antidote for bivalirudin.


76

Recommendations for

Use of Parenteral Anticoagulants in Patients

with STEMI


77

Use of Parenteral Anticoagulants in STEMI

Modified Recommendation

a. For prior treatment with UFH, additional boluses of UFH should be administered as needed to maintain therapeutic activated clotting time levels, taking into account whether GP IIb/IIIa receptor antagonists have been administered

For patients proceeding to primary PCI, who have been treated with ASA and a thienopyridine, recommended supportive anticoagulant regimens include:



78

Use of Parenteral Anticoagulants in STEMI (cont.)

Modified Recommendation

b. Bivalirudin is useful as support for primary PCI with or without prior treatment with heparin.

For patients proceeding to primary PCI, who have been treated with ASA and a thienopyridine, recommended supportive anticoagulant regimens include:



79

• Bilvalirudin added as an acceptable anticoagulant for primary PCI

• Unfractionated heparin (UFH) administration guided by:– Therapeutic activated clotting time (ACT) levels – Prior administration of GP IIb/IIIa receptor

antagonists• Enoxaparin and fondaparinux unchanged from 2007

STEMI Focused Update

Use of Parenteral Anticoagulants in STEMI Patients Proceeding to Primary PCI: Modified Class I Recommendations

HORIZONS –AMI

A Prospective, Multicenter Randomized Trial of Heparin Plus GPIIb/IIIa Inhibitors vs. Bivalirudiin STEMI: Final 3-year results from the HORIZONS-AMI Trial

Stone GW et al. Lancet 2011: Published online June 13, DOI:10.1016/S0140-6736(11)60764-2

Background

● At 1-year in the 2x2 factorial prospective, randomized HORIZONS-AMI trial:

– Bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors resulted in comparable rates of MI and stent thrombosis, with significantly reduced rates of major bleeding and mortality (all-cause and cardiac)

● 3-year results are assessed in this report

– Prespecified endpoints in the pharmacology arm at 3 years included death, reinfarction, ischemia driven target lesion revascularization, stroke, and the composite of these (MACE); non-CABG major bleeding and the composite of all net adverse clinical events (NACE).

Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…

Primary PCICABG – 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 stentPaclitaxel-eluting TAXUS stent

Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 3 years; angio FU at 13 months

Clinical FU at 30 days, 6 months, 1 year, and thenyearly through 3 years; angio FU at 13 months

Stone, GW N Engl J Med 2008;358:2218-30.

Harmonizing Outcomes with Revascularization and Stents in AMI

R 1:1

Randomized

* Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)

1-Year FU Eligible

3-Year FU

• • • • • • Withdrew • • •Withdrew • • •

• • • • • • Lost to FU • • •Lost to FU • • •

2626

4646

2222

5353

3602 pts with STEMI

• • • • • • Not true MI* • • •Not true MI* • • •2828 2929

1-Year FU

UFH + GP IIb/IIIaN=1802

BivalirudinN=1800

N=1628 N=1634

N=1774 N=1771

N=1702 N=1696

• • • • • • Withdrew • • •Withdrew • • •

• • • • • • Lost to FU • • •Lost to FU • • •1717

5757

1818

4444


3-Year Major Bleeding (non-CABG)**

* Intracranial, intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion

12

00

4

6

8

10

0.64 (0.51, 0.80)0.64 (0.51, 0.80)

2

0

1212 1515 1818 2121 2424 2727 3030 3333 3636

P=0.0001P=0.0001

3-yr HR (95%CI)3-yr HR (95%CI)

6.9%6.9%

10.5%10.5%

Maj

or B

leed

ing

(%)

Months

33 66 99

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

9.4%

6.0%


3-Year Cardiac Mortality'

5.1%%

Time in MonthsTime in Months


Car

diac

Mor

talit

y (%

)

P=0.001P=0.001

3-yr HR (95%CI)3-yr HR (95%CI)0.56 (0.40, 0.80)0.56 (0.40, 0.80)

2.9%%

0 12 15 18 21 24 27 30 33 36

Months

3 6 9

0

1

6

5

4

3

2

3.8%

2.1%


3-Year Cardiac MortalityLandmark analysis

5

4

3

2

1

0

0 3 6 9 12 15 18 21 24 27 30 33 36

Heparin + GP IIb/IIIa (n=1802)Bivalirudin (n=1800)

3 year HR (95% CI) 0.49 0.28 –0.86

p=0.01

30 day HR (95% CI) 0.62 (0.40 – 0.96)

p=0.03

2.2%

1.1%

Car

diac

mor

talit

y (%

)

1.8%

2.9%

Months


3-Year Reinfarction


6.2%

8.2%

Rei

nfar

ctio

n (%

)

00

11

22

33

44

55

66

77

88

99

1010

P=0.04

3-yr HR (95%CI)

0.76 (0.59, 0.99)

00 1212 1515 1818 2121 2424 2727 3030 3333 3636

Months

33 66 99

4.4%

3.6%


3-Year ReinfarctionLandmark analysis

10

8

6

4

2

00 3 6 9 12 15 18 21 24 27 30 33 36

3-year HR (95% CI) 0.66 (0.49 – 0.90)

p=0.007

30-day HR (95% CI)1.07 (0.66 – 1.73)

p=0.79 6.5%

4.4%

Rei

nfar

ctio

n (%

)

1.8%1.9%

9

7

5

3

1

Months

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


3-Year All-Cause Mortality or Reinfarction Landmark analysis

5

4

3

2

1

00 3 6 9 12 15 18 21 24 27 30 33 36

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

3-year HR (95% CI) 0.72 (0.58 – 0.91)

p=0.005

30-day HR (95% CI)0.84 (0.61 – 1.16)

p=0.30 10.6%

7.8%

All-

caus

e m

orta

lity

or r

einf

arct

ion

(%)

3.8%4.5%

Months


3-year MACE Components*

UFH + GPI(N=1802)

Bivalirudin(N=1800)

HR [95%CI] P ValueNumber needed to treat

Death 7.7%7.7% 5.9%5.9% 0.75 (0.58,0.97) 0.03 54

- Cardiac- Cardiac 5.1%5.1% 2.9%2.9% 0.56 (0.40,0.80) 0.001 45

- Non cardiac- Non cardiac 2.8%2.8% 3.1%3.1% 0.62

Reinfarction 8.2%8.2% 6.2%6.2% 0.76 (0.59,0.92) 0.04 52

- Q-wave- Q-wave 3.8%3.8% 3.4%3.4% 0.61

- Non Q-wave- Non Q-wave 4.9%4.9% 3.2%3.2% 0.009 58

Death or reinfarction 14.5%14.5% 11.3%11.3% 0.72 (0.58,0.91) 0.005 31

Ischemic TVR 12.1%12.1% 14.2%14.2% 0.06

Stroke 2.0%2.0% 1.7%1.7% 0.50

*Kaplan-Meier estimates, CEC adjudicated


MACE= death, reinfarction, ischemia-driven target vessel revascularization, stroke

3-year Bleeding Endpoints

UFH + GPI(N=1802)

Bivalirudin(N=1800)

HR (95% CI) P ValueNumber needed to treat

Major bleeding, non-CABG 10.5%10.5% 6.9%6.9% 0.64 (0.51-0.80) 0.0001 28

Major bleeding, including CABG 12.8%12.8% 8.9%8.9% <0.0001 25

Blood transfusion 5.1%5.1% 3.5%3.5% 0.01 61

TIMI Major or Minor 10.9%10.9% 7.0%7.0% <0.0001 26

TIMI Major 6.1%6.1% 4.1%4.1% 0.007 51

TIMI Minor 5.0%5.0% 3.2%3.2% 0.007 56

GUSTO (any) 12.7%12.7% 8.8%8.8% 0.0001 26

GUSTO severe/life-threatening 0.9%0.9% 1.0%1.0% 0.74

GUSTO moderate 6.3%6.3% 4.7%4.7% 0.03 63

GUSTO mild 6.2%6.2% 4.0%4.0% 0.003


3-Year Stent Thrombosis(ARC Definite/Probable)

66

00

22

33

44

55

0.89 (0.65, 1.23)

11

00

1212 1515 1818 2121 2424 2727 3030 3333 3636

p=0.49

HR (95%CI)

4.5% 5.1%

Ste

nt T

hrom

bosi

s (%

)

MonthsMonths

33 66 99


3.5%3.5%

3.0%3.0%


ARC= Academic Research Consortium

Conclusions: Pharmacology Randomization

● In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in:

– A significant 36% reduction in major bleeding and a significant 24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke

– A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life)



The most recent phase 3 trial of bivalirudin is the Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction (HORIZONS AMI) trial.

Randomized 3602 patients with STEMI undergoing primary PCI to either UFH+GPI or bivalirudin.

Both 30-day major bleeding and 30-day NACE served as the primary end points.

There was a significantly lower rate of both the primary bleeding end point (4.9% bivalirudin versus 8.3% UFH+GPI, P<0.001) and the primary NACE end point (9.2% versus 12.1%, P=0.005) among patients assigned to bivalirudin.

The 30-day ischemic end points of death, MI, urgent target vessel revascularization, or stroke were nearly identical between the 2 arms (5.4% versus 5.5%, P=0.95).


Two interesting divergent outcomes also were seen in the HORIZONS AMI trial: a significant increase in 24-hour (ie, acute) stent thrombosis in the bivalirudin arm (1.3% versus 0.3%, P<0.001) but a significant reduction in 30-day mortality in the bivalirudin arm (2.1% versus 3.1%, P=0.047).

This reduction in mortality was present at 1 year as well

OASIS-5: Efficacy at Day 9OASIS-5: Efficacy at Day 9

EnoxEnox FondaFonda————%——%——

Death/MI/RIDeath/MI/RI 5.85.8 5.95.9

Death/MIDeath/MI 4.14.1 4.14.1

DeathDeath 1.91.9 1.81.8

MIMI 2.72.7 2.72.7

Refractory Refractory IschemiaIschemia

1.91.9 2.052.05

0.80.8 11 1.21.2

Non-inferiorityNon-inferiorityMargin = 1.185Margin = 1.185

Hazard RatioHazard Ratio

Fonda BetterFonda Better Enox BetterEnox Better

Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76

OASIS-5: Bleeding Rates at Day 9OASIS-5: Bleeding Rates at Day 9

OutcomeOutcome EnoxEnox FondaFonda HR (95% CI)HR (95% CI) PP

No. RandomizedNo. Randomized 10,02110,021 10,05710,057

Total Bleed (%)Total Bleed (%) 7.07.0 3.23.2 0.44 (0.39 – 0.51)0.44 (0.39 – 0.51) < 0.0001< 0.0001

Major Bleed (%)Major Bleed (%) 4.04.0 2.12.1 0.53 (0.45 – 0.62)0.53 (0.45 – 0.62) < 0.0001< 0.0001

TIMI Major Bleed (%)TIMI Major Bleed (%) 1.31.3 0.70.7 0.54 (0.41 – 0.73)0.54 (0.41 – 0.73) < 0.0001< 0.0001

Minor Bleed (%)Minor Bleed (%) 3.13.1 1.11.1 0.35 (0.28 – 0.43)0.35 (0.28 – 0.43) < 0.0001< 0.0001


OASIS-5OASIS-5 Efficacy End Points at 6 MonthsEfficacy End Points at 6 Months

End point End point EnoxaparinEnoxaparin FondaparinuxFondaparinux P valueP value

Death/MI/ refractory Death/MI/ refractory ischemia ischemia 13.2%13.2% 12.3%12.3% 0.060.06

Death/MI Death/MI 11.4%11.4% 10.5%10.5% 0.050.05

Death Death 6.5% 6.5% 5.8%5.8% 0.050.05

MI MI 6.6%6.6% 6.3%6.3% NSNS

Stroke Stroke 1.7%1.7% 1.3%1.3% 0.040.04

Death/MI/stroke*Death/MI/stroke* 12.5%12.5% 11.3%11.3% 0.0070.007


PCI — Procedural ComplicationsPCI — Procedural Complications

Events (30 Days)Events (30 Days) Enoxaparin Enoxaparin n=3089n=3089

Fondaparinux Fondaparinux n=3118n=3118 P valueP value

Any UFH during PCI Any UFH during PCI 53.8%53.8% 18.8%18.8%

Any procedural Any procedural complication complication 8.6%8.6% 9.6%9.6% 0.180.18

Abrupt closureAbrupt closure 1.1%1.1% 1.5%1.5% 0.200.20

Catheter thrombus Catheter thrombus 0.5%0.5% 1.3%1.3% 0.0010.001

Vascular access Vascular access 8.1%8.1% 3.3%3.3% <0.0001<0.0001

Pseudo-aneurysmPseudo-aneurysm 1.6%1.6% 1.0%1.0% 0.390.39

Large hematomaLarge hematoma 4.4%4.4% 1.6%1.6% <0.0001<0.0001


Organization for the Assessment of Strategies Organization for the Assessment of Strategies for Ischemic Syndromes 6 (OASIS-6) Trialfor Ischemic Syndromes 6 (OASIS-6) Trial

Organization for the Assessment of Strategies Organization for the Assessment of Strategies for Ischemic Syndromes 6 (OASIS-6) Trialfor Ischemic Syndromes 6 (OASIS-6) Trial

Presented atPresented atThe American College of Cardiology The American College of Cardiology

Scientific Session 2006Scientific Session 2006

Presented by Dr. Salim YusufPresented by Dr. Salim Yusuf

OASIS - 6 TrialOASIS - 6 TrialOASIS - 6 TrialOASIS - 6 Trial

www. Clinical trial results.org

OASIS - 6 Trial: BackgroundOASIS - 6 Trial: BackgroundOASIS - 6 Trial: BackgroundOASIS - 6 Trial: Background

•The goal of the trial was to evaluate treatment The goal of the trial was to evaluate treatment with fondaparinux compared with control (unfractionated with fondaparinux compared with control (unfractionated heparin or placebo) among patients with STEMI. heparin or placebo) among patients with STEMI.

•Patients were separated into Stratum 1 (control Patients were separated into Stratum 1 (control group inelligible for UFH treatment, in other words group inelligible for UFH treatment, in other words fondaparinux was compared to placebo) and Stratum 2 fondaparinux was compared to placebo) and Stratum 2 (active control group was UFH) (active control group was UFH)

•Also, there was a PCI substudy that assessed the Also, there was a PCI substudy that assessed the efficacy of fondaparinux in Stratum 1 and Stratum 2 in the efficacy of fondaparinux in Stratum 1 and Stratum 2 in the primary PCI setting.primary PCI setting.

•The goal of the trial was to evaluate treatment The goal of the trial was to evaluate treatment with fondaparinux compared with control (unfractionated with fondaparinux compared with control (unfractionated heparin or placebo) among patients with STEMI. heparin or placebo) among patients with STEMI.

•Patients were separated into Stratum 1 (control Patients were separated into Stratum 1 (control group inelligible for UFH treatment, in other words group inelligible for UFH treatment, in other words fondaparinux was compared to placebo) and Stratum 2 fondaparinux was compared to placebo) and Stratum 2 (active control group was UFH) (active control group was UFH)

•Also, there was a PCI substudy that assessed the Also, there was a PCI substudy that assessed the efficacy of fondaparinux in Stratum 1 and Stratum 2 in the efficacy of fondaparinux in Stratum 1 and Stratum 2 in the primary PCI setting.primary PCI setting.

Presented at ACC 2006Presented at ACC 2006


OASIS – 6 Trial: Study DesignOASIS – 6 Trial: Study DesignOASIS – 6 Trial: Study DesignOASIS – 6 Trial: Study Design


Primary Endpoint: Composite of death or reinfarction at 30 daysPrimary Endpoint: Composite of death or reinfarction at 30 days Secondary Endpoint: Composite of death or reinfarction at 9 days and at final Secondary Endpoint: Composite of death or reinfarction at 9 days and at final

follow-upfollow-up

Primary Endpoint: Composite of death or reinfarction at 30 daysPrimary Endpoint: Composite of death or reinfarction at 30 days Secondary Endpoint: Composite of death or reinfarction at 9 days and at final Secondary Endpoint: Composite of death or reinfarction at 9 days and at final

follow-upfollow-up

12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial)

Randomized. Blinded. Factorial.28% female, mean age 62 years, mean follow-up 3-6 months

12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial)

Randomized. Blinded. Factorial.28% female, mean age 62 years, mean follow-up 3-6 months

Stratum 1 (No UFH)

Stratum 1 (No UFH)

Stratum 2 (UFH)Stratum 2 (UFH)

Fondaparinux2.5mg/day for up to 8

days or hospital discharge

Fondaparinux2.5mg/day for up to 8


PlaceboPlacebo Fondaparinux 2.5mg/day for up to 8


Fondaparinux 2.5mg/day for up to 8


UFHUFH


OASIS – 6 Trial: Primary EndpointOASIS – 6 Trial: Primary EndpointOASIS – 6 Trial: Primary EndpointOASIS – 6 Trial: Primary Endpoint


• The primary The primary endpoint was endpoint was lower in the lower in the fondaparinux fondaparinux group compared group compared with the control with the control group (9.7% group (9.7% vs.11.2%, HR vs.11.2%, HR 0.86, p=0.008)0.86, p=0.008)

• The results were The results were similar at 9 days similar at 9 days (HR 0.83, (HR 0.83, p=0.003) and at p=0.003) and at study end (HR study end (HR 0.88, p=0.008)0.88, p=0.008)

9.7%

7.4%

13.4%

11.2%

8.9%

14.8%

0%

3%

6%

9%

12%

15%

30 days 9 days 3-6 months

Fondaparinux (n=6036) Control (n=6056)

9.7%

7.4%

13.4%

11.2%

8.9%

14.8%

0%

3%

6%

9%

12%

15%

30 days 9 days 3-6 months

Fondaparinux (n=6036) Control (n=6056)

Primary Endpoint: Death/Reinfarction (%)

p=0.00p=0.0088

p=0.00p=0.0033

p=0.00p=0.0088

Fre

quen

cyF

requ

ency


OASIS – 6 Trial: Primary Endpoint (cont.)OASIS – 6 Trial: Primary Endpoint (cont.)OASIS – 6 Trial: Primary Endpoint (cont.)OASIS – 6 Trial: Primary Endpoint (cont.)


11.2%

14.0%

0%

2%

4%

6%

8%

10%

12%

14%

Fondaparinux Placebo

11.2%

14.0%

0%

2%

4%

6%

8%

10%

12%

14%

Fondaparinux Placebo

Reduction in Death/MI: Stratum 1Reduction in Death/MI: Stratum 1(No UFH indicated)(No UFH indicated)

p<0.05p<0.05

Reduction in Death/MI: Stratum 2Reduction in Death/MI: Stratum 2(UFH Indicated)(UFH Indicated)

p=NSp=NS

• The reduction in the primary endpoint at 30 days in the Fondaparinux group The reduction in the primary endpoint at 30 days in the Fondaparinux group was driven by Stratum 1, where death/MI occurred less frequently among Fonda was driven by Stratum 1, where death/MI occurred less frequently among Fonda pts than Placebo (11.2 vs. 14%, HR 0.79, p<0.05)pts than Placebo (11.2 vs. 14%, HR 0.79, p<0.05)• There was no difference in Stratum 2, comparing those patients who received There was no difference in Stratum 2, comparing those patients who received Fondaparinux vs those who received UFH (8.3% vs. 8.7%, HR 0.96, p=NS)Fondaparinux vs those who received UFH (8.3% vs. 8.7%, HR 0.96, p=NS)

p=0.97p=0.97

8.3% 8.7%

0%

2%

4%

6%

8%

10%

12%

14%

Fondaparinux UFH

8.3% 8.7%

0%

2%

4%

6%

8%

10%

12%

14%

Fondaparinux UFH


7.8%

2.5%

8.9%

3%

0%

2%

4%

6%

8%

10%

Death ReinfarctionFondaparinux Control

7.8%

2.5%

8.9%

3%

0%

2%

4%

6%

8%

10%

Death ReinfarctionFondaparinux Control

OASIS – 6 Trial: Primary Composite EndpointOASIS – 6 Trial: Primary Composite EndpointOASIS – 6 Trial: Primary Composite EndpointOASIS – 6 Trial: Primary Composite Endpoint

• Among the Among the components of the components of the composite at 30 composite at 30 days, mortality was days, mortality was lower in the lower in the fondaparinux group fondaparinux group compared to the compared to the control group (7.8% control group (7.8% vs. 8.9%, HR 0.87, vs. 8.9%, HR 0.87, p=0.03).p=0.03).

• Reinfarction was Reinfarction was also lower in the also lower in the fondaparinux group fondaparinux group compared to the compared to the control group (2.5% control group (2.5% vs. 3.0% HR 0.81, vs. 3.0% HR 0.81, p=0.06).p=0.06).Presented at ACC 2006Presented at ACC 2006

Components of Primary Composite Endpoint (%)

p=0.03p=0.03

p=0.06p=0.06


OASIS - 6 Trial: PCI Substudy at 30 DaysOASIS - 6 Trial: PCI Substudy at 30 DaysOASIS - 6 Trial: PCI Substudy at 30 DaysOASIS - 6 Trial: PCI Substudy at 30 Days


• There was no difference There was no difference in the primary endpoint in the primary endpoint for patients who were for patients who were managed with primary managed with primary PCI (6.1% vs 5.1%, PCI (6.1% vs 5.1%, p=0.19).p=0.19).

• Guiding catheter Guiding catheter thrombosis in the thrombosis in the primary PCI cohort primary PCI cohort occurred more often with occurred more often with fondaparinux compared fondaparinux compared with control (n=22 vs. with control (n=22 vs. n=0, p<0.001)n=0, p<0.001)

6.1%5.1%

0%

2%

4%

6%

8%

Fondaparinux Control

6.1%5.1%

0%

2%

4%

6%

8%


Primary Endpoint of Death or MI in PCI Cohort (%)

p=0.19


OASIS - 6 Trial: PCI Substudy (cont.)OASIS - 6 Trial: PCI Substudy (cont.)OASIS - 6 Trial: PCI Substudy (cont.)OASIS - 6 Trial: PCI Substudy (cont.)


• There was no There was no difference in difference in severe bleeding at severe bleeding at 9 days by 9 days by treatment grouptreatment group(1.0% (1.0% Fondaparinux vs. Fondaparinux vs. 1.3% control, 1.3% control, p=NS) p=NS)

• Intracranial Intracranial hemorrhage hemorrhage occurred in 0.2% occurred in 0.2% in each groupin each group

1.0%

1.3%

0%

1%

2%


1.0%

1.3%

0%

1%

2%


Severe Bleeding at 9 days (%)p=NS




• There was a higher There was a higher instance of instance of guiding catheter guiding catheter thrombosis in the thrombosis in the PCI cohort treated PCI cohort treated with fondaparinux with fondaparinux compared to compared to control (n=22 vs. control (n=22 vs. n=0, p<0.001)n=0, p<0.001)

22

00

5

10

15

20

25


22

00

5

10

15

20

25


Guiding Catheter Thrombosis p<0.001




• Coronary Coronary complications complications occurred in more occurred in more patients treated patients treated with fondaparinux with fondaparinux compared to compared to control (n=270 vs. control (n=270 vs. n=225, p=0.04)n=225, p=0.04)

• Coronary Coronary complications complications include abrupt include abrupt closure, no reflow, closure, no reflow, dissection, new dissection, new angiographic angiographic thrombus, thrombus, perforation, or perforation, or catheter thrombuscatheter thrombus

270

225

0

40

80

120

160

200

240

280


270

225

0

40

80

120

160

200

240

280


Coronary Complications p=0.04


OASIS – 6 Trial: ConclusionsOASIS – 6 Trial: ConclusionsOASIS – 6 Trial: ConclusionsOASIS – 6 Trial: Conclusions

•The benefit of Fondaparinux was The benefit of Fondaparinux was confined to patients in Stratum 1 where placebo confined to patients in Stratum 1 where placebo or no antithrombin was administeredor no antithrombin was administered

•Fondaparinux was not superior to Fondaparinux was not superior to active control UFHactive control UFH

•Fondaparinux was associated with a Fondaparinux was associated with a hazard in those patients who underwent PCI hazard in those patients who underwent PCI including guiding catheter thrombosisincluding guiding catheter thrombosis

•The benefit of Fondaparinux was The benefit of Fondaparinux was confined to patients in Stratum 1 where placebo confined to patients in Stratum 1 where placebo or no antithrombin was administeredor no antithrombin was administered

•Fondaparinux was not superior to Fondaparinux was not superior to active control UFHactive control UFH

•Fondaparinux was associated with a Fondaparinux was associated with a hazard in those patients who underwent PCI hazard in those patients who underwent PCI including guiding catheter thrombosisincluding guiding catheter thrombosis


Bivalirudin: A Guidelines-Supported Bivalirudin: A Guidelines-Supported Alternative to UFH/LMWH in ACSAlternative to UFH/LMWH in ACS

► Advantages of the direct thrombin inhibitor Advantages of the direct thrombin inhibitor bivalirudinbivalirudin No requirement for antithrombin IIINo requirement for antithrombin III Effective on clot-bound thrombinEffective on clot-bound thrombin Inhibits thrombin-mediated platelet activationInhibits thrombin-mediated platelet activation No interactions with PF- 4No interactions with PF- 4 Plasma half-life 25 minutesPlasma half-life 25 minutes No requirement for anticoagulant monitoringNo requirement for anticoagulant monitoring

► Clinical results with bivalirudin in PCIClinical results with bivalirudin in PCI Similar protection from ischemic events as UFH + GP IIb/IIIa Similar protection from ischemic events as UFH + GP IIb/IIIa

inhibitors, with markedly reduced bleedinginhibitors, with markedly reduced bleeding11

► Not previously tested in contemporary ACS patientsNot previously tested in contemporary ACS patients

► Advantages of the direct thrombin inhibitor Advantages of the direct thrombin inhibitor bivalirudinbivalirudin No requirement for antithrombin IIINo requirement for antithrombin III Effective on clot-bound thrombinEffective on clot-bound thrombin Inhibits thrombin-mediated platelet activationInhibits thrombin-mediated platelet activation No interactions with PF- 4No interactions with PF- 4 Plasma half-life 25 minutesPlasma half-life 25 minutes No requirement for anticoagulant monitoringNo requirement for anticoagulant monitoring

► Clinical results with bivalirudin in PCIClinical results with bivalirudin in PCI Similar protection from ischemic events as UFH + GP IIb/IIIa Similar protection from ischemic events as UFH + GP IIb/IIIa

inhibitors, with markedly reduced bleedinginhibitors, with markedly reduced bleeding11

► Not previously tested in contemporary ACS patientsNot previously tested in contemporary ACS patients

REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.


Glycoprotein IIb–IIIa inhibitors Several randomized trials have been conducted in primary

angioplasty, the vast majority of them on abciximab.

In the largest trial, the CADILLAC, a total of 2082 patients were randomized to stent or balloon with or without periprocedural administration of abciximab.

Abciximab did not improve myocardial perfusion as evaluated by myocardial blush grade and ST-segment resolution.

Some benefits in mortality with abciximab were observed in patients undergoing balloon angioplasty only, whereas no benefits were observed in terms of re-infarction.

Abciximab did not increase the risk of bleeding complications.


Periprocedural abciximab administration is associated with a significant reduction in mortality and re-infarction, without an increased risk of major bleeding complications.

Data from the BRAVE-3 trial have shown no benefits in infarct size and 30-day mortality when a clopidogrel loading dose of 600 mg was administrated.

Keeping in mind the relationship between the risk profile and mortality benefits from abciximab administration, it may be claimed that the absence of benefits would have been expected in a population with the mortality lower than 3%, as observed in the BRAVE-3 trial.


In the STRATEGY trial, no difference in death and or re-infarction was observed between high-dose tirofiban and abciximab.

Further benefits may be expected by adjunctive intracoronary administration of Gp IIb–IIIa inhibitors.

A small randomized trial showed that selective intracoronary administration of abciximab distally to the occlusion (through an over-the-wire balloon) was associated with a significant improvement in myocardial perfusion and smaller infarct size


On-TIME trial, a total of 507 STEMI patients transferred to a PCI centre were randomized to early, pre-hospital initiation of tirofiban (early) or to its initiation in the catheterization laboratory (late).

Early tirofiban was associated with a better pre-procedural TIMI 2–3 flow (43 vs. 34%, P ¼ 0.04), and myocardial perfusion (myocardial blush grade 2–3: 30 vs. 22%, P ¼ 0.04).

However, no benefits were observed in post-procedural TIMI 3 flow, myocardial perfusion, mortality (4.5 vs. 3.7%, P ¼ 0.66), and re-infarction (2.4 vs. 3.7%, P ¼ 0.43) at 1-year follow-up.

Similar results have been observed in the TITAN-TIMI 34, where 316 STEMI patients were randomized to early or late eptifibatide.


In the large FINESSE trial, up to 2500 STEMI patients were randomized within 6 h from symptom onset to facilitation with half lytic and abciximab, early or periprocedural abciximab administration.

When compared with late administration, early abciximab did improve neither pre-procedural TIMI 2–3 flow (26 vs. 25%) nor 90 day mortality (5.5 vs. 4.5%), with a non-significantly higher risk of major bleeding complications (4.1 vs. 2.6%).

A recent individual patients’ data meta-analysis (including 1662 patients) of randomized trials comparingearly vs. late administration of Gp IIb–IIIa inhibitors in primary angioplasty114 has demonstrated significant benefits in pre-procedural TIMI flow with all the molecules.


However, only abciximab was associated with significant benefits in post-procedural TIMI flow, myocardial blush, distal embolization, and survival.

For years, there have been concerns about the combination of thrombolysis and mechanical reperfusion in STEMI due to the fact that thrombolytic therapy may induce platelet aggregation and impair the results of adjunctive mechanical revascularization.

However, the results of trials on adjunctive thrombolytic therapy have been negative.

These data may be explained by the higher rates of early

reocclusion and re-infarction, potentially due to the low-rate of abciximab administration.


Data from the FINESSE trial showed that, despite improvement in pre-procedural TIMI flow, combotherapy did not confer any benefit in terms of survival, but was associated with higher risk of major bleeding complications


PCI of Non Infarct Arteries PCI of a noninfarct artery at the time of

primary PCI in stable patients is associated with worse clinical outcomes unless

The patient is in cardiogenic shock where PCI of a severe stenosis in a coronary artery supplying a large territory of myocardium might improve hemodynamic stability.

Delayed PCI can be performed in noninfarct arteries at a later time if clinically indicated


Cardiogenic Shock: Recommendations


Mechanical complications:

Echocardiography should always be performed in acute heart failure (AHF) to assess LV function and to rule out life-threatening mechanical complications that may require surgery such as acute MR secondary to papillary muscle rupture,VSD, free wall rupture, or cardiac tamponade.

The natural history of these conditions is characterized by a rapid downhill course and medical treatment alone results in close to 100% mortality.

Incidence of Post MI VSD 0.2%.

With persistent haemodynamic deterioration despite the presence of an intra-aortic balloon pump (IABP), surgery should be performed as soon as possible.





Cardiogenic shock is the leading cause of in-hospital mortality complicating STEMI.

Revascularization is the only treatment proven to decrease mortality rates.

Although revascularization is almost always accomplished through PCI, selected patients with severe 3-vessel or left main disease can benefit from emergency CABG.

Revascularization attempts may be futile and not indicated in cases of severe multiorgan failure.

Patient selection for revascularization is more important in the elderly, but several observational reports demonstrate acceptable outcomes in patients with few comorbidities and a reasonable potential for survival


Patients with cardiogenic shock should receive standard pharmacological therapies, including aspirin, a P2Y12 receptor antagonist, and anticoagulation.

Inotropic and vasopressor therapy improves perfusion pressure.

Historically, negative inotropes and vasodilators are avoided.

GP IIb/IIIa inhibitors have been shown to provide benefit in observational studies but not in 1 small RCT. (Thiele H, Allam B, Chatellier G, et al. Shock in acute myocardial infarction: the Cape Horn for trials? Eur Heart J. 2010;31:1828 –35.)


Endotracheal intubation and mechanical ventilation with positive end-expiratory pressure is usually necessary in patients with respiratory failure.

Placement of a temporary pacemaker is indicated for patients with bradycardia or high-degree atrioventricular heart block.

A pulmonary artery catheter can provide information to dose and titrate inotropes and pressors.

Further hemodynamic support is available with IABP counterpulsation or percutaneous LV assist devices, although no data support a reduction in mortality rates


Contrast medium injections should be minimized.

Orthogonal angiograms of the left coronary artery and a left anterior oblique angiogram of the right coronary artery are usually sufficient to identify the infarct artery.

Although most patients undergoing revascularization will receive a stent as part of the procedure, there are conflicting data on the impact of stenting over balloon angioplasty.



Multivessel disease In patients with multivessel disease, revascularization of

the noninfarct artery may be necessary to maximize myocardial perfusion.

Alternatively, in patients with multivessel disease and particularly left main disease, emergency CABG as a primary reperfusion strategy may be preferred.

Refractory cardiogenic shock unresponsive to revascularization may necessitate institution of more intensive cardiac support with a ventricular assist device or other hemodynamic support devices to allow for myocardial recovery or subsequent cardiac transplantation in suitable patients.



Results: Seventeen of 18 patients (94.4%) experienced pulmonary

edema (including 14 patients in cardiogenic shock). Six patients (33.3%) sustained sudden death due to

malignant ventricular tachyarrhythmias. Coronary angiography showed that there were variable

grade flow of intercoronary collaterals in 12 patients (66.7%), a totally occluded LMCA in 8 patients (44.4%), an incompletely occluded LMCA in 10 patients (55.6%), and a dominant right coronary artery (RCA) in 16 patients (88.9%).

Primary angioplasty of the LMCA was performed with a 72.2% procedural

success rate. Four patients (22.2%) received coronary artery bypass

surgery after angioplasty.


Six patients (33.3%) died in the hospital. Two patients died after discharge. Ten of 18 patients (55.6%) survived in long-term

follow-up (mean SD, 44 14 months). Those patients who survived to be discharged

had significantly higher combined coexisting incidence of intercoronary collaterals, dominant RCA, and incompletely occluded LMCA (100% vs 0.0%, p 0.0006)

than those patients who died in the hospital.


Conclusions: Acute obstructive LMCA disease generally presented as pulmonary edema, cardiogenic shock, or sudden death.

Only those who had combined coexistence of intercoronary collaterals, a dominant RCA, and an incompletely occluded LMCA could survive to be discharged.

Our experience suggests that primary LMCA angioplasty is a feasible and effective procedure, and it may save lives in this clinical setting.






175

Recommendations for Thrombus Aspiration during PCI for STEMI


176

Thrombus Aspiration During PCI for STEMI

NEW Recommendation

Aspiration thrombectomy is

reasonable for patientsundergoing primary

PCI



Distal embolization• Despite successful mechanical revascularization,

suboptimal reperfusion may occur, resulting in unfavourable outcome.

• In the last years, growing interest has been focused on the role of distal embolization as major determinant of poor reperfusion.

ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused UpdateDate of download: 11/14/2012

Copyright © The American College of Cardiology. All rights reserved.

From: Manual Thrombus-Aspiration Improves Myocardial Reperfusion: Title and subTitle BreakThe Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus-Aspiration in Primary and Rescue Angioplasty (REMEDIA) Trial

J Am Coll Cardiol. 2005;46(2):371-376. doi:10.1016/j.jacc.2005.04.057

Study flowchart. *Patients entering the intention-to-treat analysis. ECG = electrocardiogram; MBG = myocardial blush grade; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation acute myocardial infarction; STR = ST-segment resolution.

Figure Legend:





Distribution of patients according to the combination of myocardial blush grade (MBG) ≥2 and ST-segment resolution (STR) ≥70% in the thrombus-aspiration group (white bars) and the standard percutaneous coronary intervention group (black bars) (p = 0.025 using chi-square test).

Figure Legend:





Odds ratios and 95% confidence intervals for the combination of myocardial blush grade ≥2 and ST-segment resolution ≥70% in the comparison between thrombus-aspiration and standard percutaneous coronary intervention (PCI) according to key baseline clinical and angiographic variables. Cx = circumflex artery; LAD = left anterior descending artery; RCA = right coronary artery; TIMI = Thrombolysis In Myocardial Infarction.

Figure Legend:























Special Population


Those with Renal Compromise & CKD



Revascularization for acute graft failure Early graft failure after CABG (,1 month) may occur in 8–

30% of cases.

Perioperative angiography showed failure of 8% of saphenous vein grafts (SVGs) and 7% of left ITA grafts.

In symptomatic patients, early graft failure can be identified as the cause of ischaemia in 75% of cases, while pericarditis or prolonged spasm is diagnosed in the remainder.

PCI in acute post-operative graft failure may be an alternative to re-operation with acceptable results and fewer complications


The target for PCI is the body of the native vessel or of the ITA graft while freshly occluded SVG or the anastomosis itself should not be targeted due to the

risk of embolization or perforation.

Surgery should be favoured if the graft or native artery appears unsuitable for PCI, or if several important grafts are occluded.

In asymptomatic patients, re-operation or PCI should only be considered if the artery is of good size, severely narrowed and supplies a large territory of myocardium.





Distal Embolization









PercuSurge GuardWire (Medtronic, Santa Rosa, CA, USA) is an occlusion thrombectomy device that consists of a wire containing a central lumen that communicates with a lowpressure distal occlusion balloon incorporated into the tip.

The wire serves as both the angioplasty guidewire and provides protection from distal embolization.

An inflation device allows controlled expansion and sizing of the occlusion balloon in the treated vessel.

An aspiration catheter is used to remove the debris from the treated vessel before the balloon is deflated and antegrade flow in the treated vessel is restored.



AngioGuard’s technology incorporates an angioplasty guidewire with a filter that expands to 6 mm and is placed distal to the target lesion to capture and retrieve embolic debris .

At the end of the procedure, the filter is collapsed, trapping the particulate matter and facilitating removal from the artery.

The AngioGuard filter has multiple, 100 micron, laser-drilled holes that allow perfusion during device deployment.

It has been proposed that this is a major advantage of filter devices.

In contrast, the balloon occlusion devices result in complete cessation of antegrade flow for as long as it takes to treat the vessel and aspirate the debris (typically 2–3 minutes in the hands of experienced operators) .


This is a critical clinical consideration in patients with reduced left ventricular function or in patients in whom the treated artery supplies a large amount of myocardium.

Conversely, it has been proposed that incomplete vessel occlusion with the filter devices allows passage of debris through the holes of the filter devices.



Filter Wire EX™ The FilterWire EX (Boston Scientific, Natick, MA, USA) is another filter device currently under clinical investigation.

Similar to the AngioGuard, it is a low-profile (< 3.5 French) filter mounted on a 0.014 inch angioplasty wire with pore holes of

80 microns that permit antegrade blood flow while providing distal protection.

The filter design is characterized by an off-center position and ‘fish-mouth’ opening, and can be retracted into any standard angioplasty balloon.

A radiopaque nitinol framework provides filter support and facilitates fluoroscopic visualization.


Documents

ISSUES AND CONTROVERSIES IN PRIMARY PTCA