Howard C. Herrmann, MDProfessor of MedicineDirector, Interventional Cardiology and

Cardiac Catheterization LaboratoriesUniversity of Pennsylvania Medical Center

Is There a Role for Facilitated PCI in 2007?

Primary PCI vs LyticsPrimary PCI vs LyticsReview of 23 TrialsReview of 23 Trials

2%1%

0%

2%

4%

6%

8%

10%

7%

3%

0%

2%

4%

6%

8%

10%

P=0.0002Death

P=0.0004Stroke

P<0.0001Recurrent MI

Lytic PrimaryPCI

Lytic PrimaryPCI

PrimaryPCI

Keeley EC, Boura JA, Grines CL. Lancet 2003;361:13-20.

7%

9%

0%

2%

4%

6%

8%

10%

Lytic

7739 pts

SK in 8 trials

Stents in 12 trials

GP IIb/IIIa in 8 trials

•Compared onsite lysis (front-loaded tPA) with transfer for PCI (at both invasive and referring hospitals) in 1572 pts with acute MI

(sx’s < 12h, median age 63 yrs, >50% ant)

•Results (at 30 days):

tPA PCI p

D/reMI/CVA 13.7% 8.0% .0003

Death 7.6 6.6 .35

CVA 2.0 1.0 ns

•No difference between invasive and referring hospitals in terms of benefit (only 10 min faster PCI in inv centers-1 h longer than lysis)

•Few complications during transport

•Low rate of rescue PCI (2.5%) and late PCI in tPA arm (17%)

DANAMI-2 (Danish Trial in Acute MI-2)DANAMI-2 (Danish Trial in Acute MI-2)

Transfer for Primary PCI – Transfer for Primary PCI – The Importance of TimeThe Importance of Time

• Bias favoring PCI in randomized trialsBias favoring PCI in randomized trials• Overall door-to-balloon time shortOverall door-to-balloon time short

• Call ahead to activate CCLCall ahead to activate CCL• Bypass the ED, CCUBypass the ED, CCU

• Selection by exclusion pts unsafe for transferSelection by exclusion pts unsafe for transfer• Prior CVA not excluded from fibrinolysisPrior CVA not excluded from fibrinolysis

• Increased risk CVAIncreased risk CVA• Lost benefit of rescue PCILost benefit of rescue PCI

• Procedural MI not included in PCI endpointProcedural MI not included in PCI endpoint• Low rate f/u angiography increased risk re-MI (major Low rate f/u angiography increased risk re-MI (major

determinant of diff in composite endpoint)determinant of diff in composite endpoint)• Benefit PCI greatest in pts presenting >3h after Benefit PCI greatest in pts presenting >3h after

symptom onset (c/w relative greater benefit fibrinolysis symptom onset (c/w relative greater benefit fibrinolysis in early presenters)in early presenters)

Herrmann HC. Circulation 2005 (editorial)

Study (reference)Study (reference)n/n/

armarm

Total Total Symptom Symptom or Door to or Door to

Lysis Lysis (min)*(min)*

Total Total Symptom Symptom or Door or Door to PCI to PCI (min)*(min)*

Difference Difference (Transfer (Transfer

Delay) Delay) (min)(min)

Door to Door to balloon in balloon in Tx Hosp Tx Hosp

(min)(min)

Absolute Absolute Risk Risk

Reduction Reduction Death (%, Death (%,

30 d)30 d)

Absolute Absolute Risk Risk

Reduction Reduction MI (%, 30 d)MI (%, 30 d)

Vermeer (15)Vermeer (15) 7575 135135 230230 9595 NANA 00 66

Prague 1 (13)Prague 1 (13) 100100 2222 9595 7373 2828 77 99

Prague 2 (16)Prague 2 (16) 425425 185185 280280 9595 2626 3.23.2 1.71.7

AIR-PAMI (17)AIR-PAMI (17) 6969 6363 174174 111111 3838 3.73.7 -1.4-1.4

DANAMI (18)DANAMI (18) 786786 166166 214214 4848 2626 1.21.2 4.74.7

TOTAL (weighted TOTAL (weighted average)average) 14551455 155.2155.2 224.0224.0 68.968.9 25.425.4 2.22.2 3.93.9

Nallamothu (22)**Nallamothu (22)** 42784278 -- 287#287# 120120 5353 -- --

*Symptom to therapy in *Symptom to therapy in trials 15, 16, 18; door to trials 15, 16, 18; door to therapy in trials 13, 17.therapy in trials 13, 17.

# data available in 82% of # data available in 82% of patientspatients

** Data provided by H. ** Data provided by H. Krumholz, MD (personal Krumholz, MD (personal communication)communication)

Transfer for Primary PCI – The Importance of TimeTransfer for Primary PCI – The Importance of Time

Nallamothu et al, Circ 2005; 111: 761-767Herrmann HC, Circ 2005; 111: 718

Effect of Treatment Delay on Outcome Effect of Treatment Delay on Outcome with Primary PCIwith Primary PCI

• Time to reperfusion after fibrinolysis is a Time to reperfusion after fibrinolysis is a critical determinant of outcomecritical determinant of outcome

• In some reports, time to reperfusion with In some reports, time to reperfusion with primary angioplasty has had little effect primary angioplasty has had little effect on mortality (Brodie, AJC 2001;88:1085)on mortality (Brodie, AJC 2001;88:1085)

• In most other studies*, however, longer In most other studies*, however, longer door-to-balloon time worsens outcome door-to-balloon time worsens outcome as assessed by infarct size and mortalityas assessed by infarct size and mortality

*Angeja, AJC 2002;89:1156 Liem, JACC 1998;32:629Berger, Circ 1999;100:14 Cannon, JAMA 2000;283:2941DeLuca, Circ 2004;109:1223 Nallamothu, AJC 2003;92:824

Treatment Delay Reduces Benefit Treatment Delay Reduces Benefit With Both Lysis and PCI With Both Lysis and PCI

010203040506070

0 - 1 1 - 2 2 - 3 3 - 6 6 - 12 12 - 24

ADDITIONAL LIVES SAVED / 1000 LYSED(meta-analysis 22 trials, n = 50,246 pts)

Time from onset symptoms (h)

Boersma, Lancet 1996;348:771Boersma, Lancet 1996;348:771

0.6

1

1.4

1.8

2.2

0 - 60 61 - 90 91 -120

121 -150

151 -180

> 180

Door to Balloon Time, N = 27,080Adjusted OR in-hosp mortality

Time (mins)

Cannon et al., JAMA 2000;283:2941Cannon et al., JAMA 2000;283:2941

Time to Treatment Increases Mortality in Time to Treatment Increases Mortality in Primary AngioplastyPrimary Angioplasty

De Luca et al., Circ 2004;109:1223De Luca et al., Circ 2004;109:1223

•1791 STEMI pts (1-year mort of 5.8%)

•Previous studies:lower risklong door-to-balloon times

•Time to treatment = symptom onset to 1st balloon inflation

After adjustment, every 30 min delay increased the risk of 1-year mortality by 7.5%

PCI vs Lysis: Is Timing (Almost) Everything ?

23 RCTs

For every 10 min delay to PCI: 1 % reduction in Mortality Diff

N= 7419

Nallamothu and Bates , AJC 92: 824, 2003

Steg et al, Circ 2003;108:2851

CAPTIM Trial: Outcome by time to randomization

•Multicenter French study

•840 AMI pts (<6h)

•Randomized to pre-hosp lysis (acc t-PA) with transfer to cath capable hospital vs PCI

The Case for Facilitated PCIThe Case for Facilitated PCI• Real world transfer times greatly exceed those in Real world transfer times greatly exceed those in

randomized trialsrandomized trials• New paradigms may be necessary to justify delayed PCINew paradigms may be necessary to justify delayed PCI

• Improve systems and processes of care to reduce Improve systems and processes of care to reduce door-to-balloon timedoor-to-balloon time

• Optimize communicationOptimize communication• Centers of excellence to regionalize specialized and/or Centers of excellence to regionalize specialized and/or

expensive adjunctive therapiesexpensive adjunctive therapies• Treatment on the way – Facilitated PCI: Treatment on the way – Facilitated PCI: Early, planned PCI following a Early, planned PCI following a pharmacologic pharmacologic

regimen intended to regimen intended to open the infarct-related open the infarct-related arteryartery

COMBINATION THERAPY FOR ACUTE MI:COMBINATION THERAPY FOR ACUTE MI:Role of Adjunctive MedicationsRole of Adjunctive Medications

ISIS-2 and 3GISSI-I and 2GUSTO 1

Gold et alSPEED,TIMI 14 Substudies

PTCA: PAMI, ZWOLLE, MAYO, GUSTO IIb

STENT: PAMI, FRESCO, ZWOLLE, GRAMI

LYTICLYTIC

PCIPCI

IIB/IIIAIIB/IIIA

TIMI 14 , SPEEDINTRO-AMI, INTEGRITI

FASTER, ENTIREGUSTO 5

EPIC, GUSTO IIIRAPPORT, ISAR-2, ADMIRAL, STOPAM ICADILLAC

Updated from Herrmann HC. Am J Cardiol. 2000;85:10C-16C

TAMI, TIMI IIA, SWIFT, ECSG, PACT, O’Neill, PRAGUE, SIAM III, GRACIA-1/2, CAPITAL AMI, TRANSFER, ASSENT-4

LMWH: Create, ASSENT-3, ExtractDTI: Hero-2Pentasacc: OASIS 6

FACILITATED PCI

(BRAVE, CARESS, ADVANCE, TIMI 34,

ASSENT 4,FINESSE)

Potential Benefits of Facilitated PCIPotential Benefits of Facilitated PCI

• May be cost-effective if combination pharmacologic therapy lessens the need for PCI

• Improves patient stability during intervention• Patients with open arteries have less shock, IABP,

pacer, arrest• Higher technical success due to less hectic

procedure, better distal vessel visualization• Fuses best aspects of lysis and 1° PCI

• Earlier and greater TIMI 3 flow rates• May improve myocardial tissue perfusion

HYPOTHETICAL TIMI 3 FLOWHYPOTHETICAL TIMI 3 FLOW

0102030405060708090

100

-30 0 30 60 90

86% Fac PCI86% Fac PCI77% Combo Rx77% Combo Rx70%70% 1° PTCA1° PTCA60%60% LysisLysis

EARLY LATERBEGIN Rx

ARRIVE ED

Percent of Patients with TIMI 3 Flow

TIME (mins)

21.1

2.5*

12.4

8.3

23.7

2.5*

13.39.2

0

5

10

15

20

25

PRE/ER CCU/CCL PRE/ER CCU/CCL

Placebo Abciximab

30 days 6 months

Facilitation with GP IIb/IIIaFacilitation with GP IIb/IIIaADMIRAL: Pre-hospital Phase ADMIRAL: Pre-hospital Phase

• Randomized AMI Randomized AMI study 1° stent study 1° stent (n=300)(n=300)

• 50% reduction in 150% reduction in 100 composite of D, reMI, composite of D, reMI, urgent TVR at 30durgent TVR at 30d

• 11% received pre-11% received pre-hosp Ab or placebo hosp Ab or placebo (57 min earlier); (57 min earlier); 15% in ER:15% in ER:

• Greater TIMI3 Greater TIMI3 flowflow

• Better LVEFBetter LVEF

Ecollan and Montalscot, NEJM 2001;344:1895-1903

30 day Endpoint (D, MI, UReV)

Facilitation with Lytic: Immediate vs Delayed PTCA After LyticImmediate vs Delayed PTCA After LyticImmediate PTCA With or Without LyticImmediate PTCA With or Without Lytic

11

3

23

14

73

21

710

2

15

8

0

10

20

30Immediate PTCA With LyticDelayed PTCA Without Lytic

Early Endpoint (< 30 d)

TRIAL:TRIAL: TAMI TIMI IIA ECSG Swift O’Neill Prague YEAR:YEAR: 1987 1988 1988 1991 1992 1998 LYTIC:LYTIC: tPA tPA tPA Anistk SK SK N:N: 197 389 367 800 122 201 DELAY:DELAY: 7-10d 18-48h ETT ETT None Transfer ENDPT:ENDPT: D/CABG D/CABG D D/CABG CABG D/MI/CVA

New Lytic-Based Facilitated PCI TrialsNew Lytic-Based Facilitated PCI Trials

Early vs Late PCI Lytic or No Lytic Pre-PCI

(all pts get lysed) (all pts get PCI)

SIAM III

GRACIA-1

CAPITAL AMI

TRANSFER-AMI

GRACIA-2

ASSENT-4

Recent Trials of Facilitated PCI With Full-Dose FibrinolyticRecent Trials of Facilitated PCI With Full-Dose Fibrinolytic(Early vs Later PCI; All Pts Received Lytic)(Early vs Later PCI; All Pts Received Lytic)

TRIAL:TRIAL: CAPITAL AMI SIAM III GRACIA-1 YEAR:YEAR: 2005 2003 2004 LYTIC:LYTIC: TNK r-PA “fibrin-specific” N:N: 170 163 500 PCI Time:PCI Time: 132 min 3.5 h 19.6 h ENDPT:ENDPT: D, re-MI/ACS, CVA D, re-MI/ACS D, re-MI/ACS, TVR

Major driver of reduction was recurrent ischemia

CARESS in AMICARESS in AMI(Combined Abciximab RE-teplase Stent Study in AMI)(Combined Abciximab RE-teplase Stent Study in AMI)

• Objective: Compare early PCI vs conservative care after ½ dose lytic with GP IIb/IIIa

• Design: Planned 1800 high-risk AMI pts (<12 h) given ½ dose r-PA with abciximab, then randomized to PCI vs conservative care; multicenter Italy, France, Poland

• Actual: 600 patients (excluded age >75)

• 1o Endpt: D / re-MI / refractory ischemia at 30 d

• Results: Expected 12/05 – Presented 08/07

• Conclusions: Early PCI was beneficial: reduced primary endpoint from 11% to 4%, but most of benefit in reducing refractory ischemia (with no mortality benefit) at a cost of increased bleeding.

Di Mario C et al. Am Heart J. 2004;148:378-385.Results presented ESC, Vienna, Sept, 2007

ASSENT 4 PCIASSENT 4 PCI

Boehringer Ingelheim / Genentech News Release

Available at: http://www.boehringer-ingelheim.ca/news_releases/2003/2003-11-11.asp. Accessed August 19, 2004.

ASSENTASSENT--4 4 InterruptedInterrupted

Assent-4 Investigators, Lancet 2006;367:569

ASSENT-4ASSENT-4What went wrong?What went wrong?

• Imbalance between arms: more high risk patients in TNK armImbalance between arms: more high risk patients in TNK arm

• After adjustment for these differences, no mortality diff, but the After adjustment for these differences, no mortality diff, but the combined endpt of death, shock, and CHF still highercombined endpt of death, shock, and CHF still higher

• TNK less effective than usual (only 44% had TIMI-3 flow based on TNK less effective than usual (only 44% had TIMI-3 flow based on investigator reports)investigator reports)

• Time delay between TNK and PCI was shorter than expected (104 mins) Time delay between TNK and PCI was shorter than expected (104 mins) which minimizes benefit of TNK leaving complications of PCI with lytic which minimizes benefit of TNK leaving complications of PCI with lytic Low use of newer anti-platelet and anti-coagulant agents due to fear of Low use of newer anti-platelet and anti-coagulant agents due to fear of bleeding (eg., clopidogrel, IIb/IIIa, anti-thrombins)bleeding (eg., clopidogrel, IIb/IIIa, anti-thrombins)

• TNK-PCI arm outcomes similar to other lytic trials, PCI alone arm much TNK-PCI arm outcomes similar to other lytic trials, PCI alone arm much better than expectedbetter than expected

• Goal was to enroll high-risk patients with long delay to PCI, but Goal was to enroll high-risk patients with long delay to PCI, but enrollment was not such high-risk patients with short delaysenrollment was not such high-risk patients with short delays

Comparison of Outcomes in ASSENT-4 With Those in Other Trials of TNK or PCI in MI

EndpointEndpoint ASSENT-2 ASSENT-2 (n=8461) (%)(n=8461) (%)

ASSENT-3 ASSENT-3 (n=2038) (%)(n=2038) (%)

ASSENT-3+ ASSENT-3+ (n=821)(n=821)(%)(%)

ASSENT-4 ASSENT-4 TNK+PCI TNK+PCI (n=829) (%)(n=829) (%)

ASSENT-4 ASSENT-4 PCI alone PCI alone (n=836) (%)(n=836) (%)

Primary PCI Primary PCI meta meta (n=3872) (%)(n=3872) (%)

30-d death30-d death 6.26.2 6.06.0 6.06.0 6.06.0 3.83.8 7.07.0

Intracranial Intracranial hemorrhagehemorrhage

0.930.93 0.930.93 0.970.97 0.970.97 00 0.050.05

Total stroke Total stroke 1.81.8 1.71.7 1.51.5 1.81.8 00 1.11.1

Re-MIRe-MI 4.14.1 4.24.2 5.85.8 5.25.2 2.72.7 6.56.5

Major bleedMajor bleed 4.74.7 2.22.2 2.82.8 5.75.7 4.44.4 7.07.0

van de Werf F. European Society of Cardiology Congress 2005. September 4-7, 2005; Stockholm, Sweden.

3000 pts ST MIChest pain <6 h

ASA (150-325 mg)Heparin (40 U/kg, 3000) or

Enoxaparin (.5/.3 mg/kg iv/sc)

FACILITATED PCI

Abciximab (.25/.125)Reteplase (5 IU + 5 IU)

in the ED (single bolus for age>75)

PCI 60-120 mins

PRIMARY PCI

Angio/PCI 60-120 minutes

Abciximab during PCI in CCL

1° Endpoint 90 day death, CHF,

VF, shock

Double-blind, randomized, triple-dummy placebo-controlledABCIXIMAB

FACILITATED PCI

Abciximab in ERAngio/PCI

60-120 minutes

Trial Design

TIMI Flow in IRA Pre-PCITIMI Flow in IRA Pre-PCI

% Subjects with TIMI 2/3 (Patency) Pre-PCI

13%

11%

25%

36%15%

12%

0%

20%

40%

60%

80%

100%

120%

Primary PCI (in labAbciximab) (n=790)

Abciximab FacilitatedPCI (n=809)

Reteplase/AbciximabFacilitated PCI (n=815)

Perc

enta

ge

25% 26%

61%p<0.0001

p<0.0001

Ave Time from First Abciximab Bolus to Angiogram In Facilitated Groups: 74min 76min

Modified ITT Population with Index PCI: ITT, PCI and any dose of study drug (active or placebo); Investigator assessment

TIMI 3

TIMI 2

ST Segment Resolution (>70%) ST Segment Resolution (>70%) at 60-90 Min: Core Labat 60-90 Min: Core Lab

% Evaluable Subjects with ST Segment Resolution

31%23%

51%

33%24%

57%44%

36%

64%

0%

20%

40%

60%

80%

100%

All (n=745) Prior to BalloonInflation (n=525)

After BalloonInflation (n=154)

Perc

enta

ge

Primary PCI with in lab Abciximab (n=242)Abciximab Facililated PCI (n=257)Reteplase/Abciximab Facilitated PCI (n=246)

p=0.003

p=0.013

*Half of subjects randomly selected for Core Lab over-read

p=0.010

p=0.011

p=NS

Primary EndpointPrimary Endpoint

10.7%10.5%9.8%

TIMI Major or Minor BleedingTIMI Major or Minor Bleeding (nonintracranial) through Discharge/Day7 (nonintracranial) through Discharge/Day7

TIMI Bleeding through Discharge/Day 7

2.6%4.3%

6.9%4.1%

6.0%

10.1%

4.8%

9.7%

14.5%

0%

5%

10%

15%

20%

25%

30%

TIMI Major TIMI Minor TIMI Major or Minor

Perc

enta

ge

Primary PCI with In Lab Abciximab (n=795)Abciximab Facililated PCI (n=805)Abciximab/Reteplase Facilitated PCI (n=814)

p=0.025

p=0.025

p<0.001

p=0.127

p=0.008

p=0.141

p<0.001

p=0.006p=0.547

StrokeStrokeStroke through Discharge/Day 7

0.1%

0.9% 1.0%

0.0%0.0%0.5% 0.5%

0.0%

0.6% 0.5%

1.1%

0.4%

0%

1%

2%

3%

4%

5%

ICH (n=6) Ischemic (n=15) Total Stroke(n=21)

Fatal Stroke(n=3)

Perc

enta

ge

Primary PCI with In Lab Abciximab (n=795)Abciximab Facililated PCI (n=805)Reteplase/Abciximab Facilitated PCI (n=814)

p=0.062

p=0.218

p=0.497

p=NS p=NS p=NS

Timing (and Patient Selection) are the Keys to Timing (and Patient Selection) are the Keys to Benefit (or Lack Thereof) of Facilitated PCIBenefit (or Lack Thereof) of Facilitated PCI

Stone and Gersh, Lancet 2006;367:543

Copyright ©2006 American Heart Association

Pinto, D. S. et al. Circulation 2006;114:2019-2025

Adjusted analysis illustrating significant heterogeneity in the PCI-related delay (DB-DN time) for which the mortality rates with primary PCI and

fibrinolysis were comparable after the study population was stratified by prehospital delay, location of infarct, and age

ConclusionsConclusions• Primary PCI is an excellent treatment for acute MI, howeverPrimary PCI is an excellent treatment for acute MI, however

• Treatment delay reduces its benefitTreatment delay reduces its benefit• Real world transfer times for PCI are longReal world transfer times for PCI are long

• The early, planned use of PCI following a pharmacologic The early, planned use of PCI following a pharmacologic regimen intended to open the IRA has theoretical and practical regimen intended to open the IRA has theoretical and practical appealappeal• In this regard, must recognize factors which may affect outcome of In this regard, must recognize factors which may affect outcome of

this strategy: this strategy: • Ischemic timeIschemic time• Door-to- balloon time (with or without transfer)Door-to- balloon time (with or without transfer)• Size of infarctSize of infarct• Patient age / bleeding riskPatient age / bleeding risk

• However, neither abciximab nor lytic strategies have been However, neither abciximab nor lytic strategies have been shown beneficial in randomized trials and cannot be shown beneficial in randomized trials and cannot be recommended as a routine strategy.recommended as a routine strategy.

• Given the benefits observed on TIMI flow and ST seg resolution, Given the benefits observed on TIMI flow and ST seg resolution, further study of high risk patients seems warrantedfurther study of high risk patients seems warranted