The “Code White” Team of Dr. William Ganz: 1979The “Code White” Team of Dr. William Ganz: 1979

Goal of IC SK Goal of IC SK BeforeBefore PCI: Get the PCI: Get the arteryartery open openGoal of IC SK Goal of IC SK BeforeBefore PCI: Get the PCI: Get the arteryartery open open

Acute MI Treated with Distal Protection and IC tPA (8 mg)

After Percusurge / Angiojet

After 8 mg IC tPA

Pre PCI

Clot

Clot

Intracoronary Streptokinase after Primary Percutaneous Coronary

Intervention

Murat Sezer, Hüseyin Oflaz, Taner Gören, Irem Okcular, Berrin Umman, Yılmaz Nişancı, Ahmet Kaya Bilge, Yasemin Şanlı, Mehmet Meriç,

Sabahattin Umman

Istanbul University, Istanbul Faculty of Medicine, Department of Cardiology

Hypothesis

• Complementary intracoronary streptokinase (ICSK) infusion immediately following primary PCI may further improve tissue level perfusion by dissolving thrombus (either in situ formed or embolized from the proximal origin) at microvascular level.

• To this end, the effect of low-dose (250 kU) ICSK, administered immediately after primary PCI, on myocardial perfusion was investigated prospectively.

Inclusion / Exclusion Criteria

• Inclusion criteria:– Ongoing chest pain, – ST segment elevation on electrocardiogram,– Occlusion of the infarct-related artery at angiography

(Thrombolysis in Myocardial Infarction [TIMI] 0-I flow)

• Exclusion criteria:– Culprit lesion in a saphenous vein graft, – Additional narrowing >50% distal to the culprit lesion,– Left bundle branch block,– History of prior myocardial infarction, and – Contraindications to streptokinase, tirofiban, aspirin, clopidogrel

or heparin.

Patients and RandomizationImmediately after diagnostic angiography

eligible patients (n =41) were randomized to

ICSK group (n=21) Control group (n=20)

(Primary PCI + 250 kU intracoronary streptokinase) (primary PCI)

All patients recieved:

- 300 mg of aspirin,

- A loading dose of 600 mg of clopidogrel,

- Intracoronary unfractioned heparin at a dose of 100 U/kg during the procedure,

- Tirofiban as a bolus of 0.1 μg/kg in 3 minutes followed by continuous infusion of 0.15 μg/kg/min for 12 hours, and

- Low molecular weight heparin initiated four to five hours after primary PCI and continued for at least 48 hours

All patients underwent intracoronary hemodynamic measurement and angiographic analysis two days after primary PCI to evaluate microvascular function

ST segment resolution

Diastolic deceleration time

Echocardiographic assessment of left ventricular volumes and function

Coronary flow reserve

Index of microvascular resistanceCoronary wedge pressure (mean ad systolic)

Pressure derived collateral flow index

Myocardial blush grades

Corrected TIMI frame count

Study Design

Second angiography and intracoronary hemodynamic

measurements 2 days after AMI.

Ass

esin

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icro

vasc

ular

per

fusi

on

and

LV v

olum

es in

ear

ly p

hase

of

ST

EM

I

Control angiography (TIMI frame count, Myocardial blush grade) Infarct size measurement (SPECT), Echocardiographic assessment of left ventricular volumes and functionLo

ng te

rm

asse

smen

ts

(at 6

mon

ths)

Transthoracic echocardiography,

2 days after AMI

Pre/post PCI ECG

Assessment of Microvascular Perfusion by Invasive Methods• Thermodilution-derived Coronary Flow Reserve (CFR)*

= Resting mean transit time / hyperemic mean transit time *Pijls NHJ et al.. Circulation 2002;105:2482-

2486

• Index of Microvascular Resistance (IMR)**:

= Distal coronary pressure x hyperemic mean transit time**Fearon WF. et al.. Circulation. 2003;107:3129-3132

• Coronary Wedge Pressure (CWP) and Pressure-derived Collateral Flow Index (CFIp): = CWP/Pa Guiding cath.

Microvasculature

Balloon

CWP: mm Hg

Pa: mm Hg

Pressure wire

0.6116 (80%)19 (90%)ACE inhibitor

0.4412 (60%)16 (76%)Intravenous nitroglycerin

0.9618 (90%)19 (90%)Statins

120 (100%)21 (100%)Clopidogrel

120 (100%)21 (100%)GP IIb/IIIa inhibitor

120 (100%)21 (100%)LMWH

0.9618 (90%)19 (90%)Beta- Blocker

120 (100%)21 (100%)Aspirin

Concomitant medications during PCI and in the Coronary Care Unit

0.1819 ± 9.715.6 ± 10.5Initial ST elevation (mean, mm)

0,6110.4 ± 7.69.1 ± 6.5Peak troponin T

4 (20%)7 (33%)Non-anterior0.54

16 (80%)14 (67%)AnteriorInfarctlocalization

0.855 (26%)5 (24%)History of preinfarction angina

0.2714 (74%)12 (57%)Dyslipidemia

0.207 (37%)4 (19%)Hypertension

0.653 (16%)2 (10%)Diabetes Mellitus

0.6514 (70%)17 (81%)Smoking

0,981921Sex (male)

0.7952.2±10.951.4± 5.7Age (mean, yrs)

Main characteristics

p(two tailed)

Control Groupn: 20

Intracoronary Streptokinase Group

n: 21

Baseline Demographic and Clinical Characteristics.

-00Procedural complications

18 (90%)16 (77%)3

2 (10%)5 (23%)2 0.41

000 - 1

TIMI flow grades

0.593.5 ± 2.84.8 ± 2.1Mean residual stenosis, %

0.711.14 ± 0.351.21 ± 0.41Number of stents

0.2912.4 ± 2.613.4 ± 3.1Max. Inflation pressure, (atm).

12 (10%)3 (14%)Side branch embolization

0.412 (10%)5 (23%)Slow / no-reflow

Post-procedural results

0.93218.8 ± 109,8257.7 ± 211.8Pain to balloon time (minute)

1100100Baseline TIMI flow 0/1 (%)

2 (10%)1 (5%)3

4 (20%)4 (19%)2 0.73

14 (70%)16 (76%)1

Number of diseased vessels

1 (5%)1 (5%)Cx

3 (15%)6 (28%)RCA 0.54

16 (80%)14 (67%)LAD

Infarct relatedartery

Angiographic characteristics ICSK group Control group p

Angiographic Characteristics and Post Procedural Results

0.0020.17

(0.14)-(0.21)0.08

(0.05)-(0.11)<0.00

1-0.09

(-- 0.13)-(-0.06)0.17 + 0.070.08 + 0.05CFIp (mean, unitless)

<0.00129.46

(21.80)-(37.12)15.17

(8.26)-(22.08)<0.00

1-15.56

(-21.27)-(-9.85)33.80 + 11.018.24 + 6.07CWP, systolic (mmHg)

0.0412.54

(6.83)-(18.24)7.98

(2.84)-(13.12)0.004

-6.39(-10.73)-(-2.05)

17.20 + 7.9310.81 + 5.46CWP, mean (mmHg)

0.0021.66

(1.25)-(2.07)2.29

(1.92)-(2.66)<0.00

10.62

(0.35)-(0.93)1.39 + 0.312.01 + 0.57CFR

<0.00129.05

(22.17)-(35.92)11.73

(5.53)-(17.92)<0.00

1-16.20

(-21.75)(10.64)32.49 +11.0416.29 + 5.06IMR (U)

pControl

Group, Mean(95% CI)

Intracoronary Streptokinase Group, Mean

(95% CI)

pMean

Difference 95% CI

Control Groupn:20

Intracoronary Streptokinase

Groupn:21

MultivariateUnivariate

Intracoronary Hemodynamic Indices of Microvascular Perfusion

Angiographic (cTFC, MBG), Electrocardiographic (STR) and Echocardiographic (DDT) Indices of Microvascular Perfusion

0.3971.05

(53.55)-(88.55)77.26

(61.30)-(93.23)0.04

16.30(0.06)-(32.54)

51.25±24.4067.55+22.9160 minutes after primary PCI

0.4571.36

(56.66)-(86.07)66.75

(53.04)-(80.45)0.42

5.00(-7.89)-(17.89)

63.21+14.3768.21+20.13Immediately after primary PCI

STR (%)

0.001257

(-65)-(580)750

(446)-(1054)<0.001

468(261)-(676)

360+292828+258DDT in the LAD artery (milliseconds)#

---7 (53.8)11 (91.7)2/3

0.13

--

0.035

-6 (46.2)1 (8.3)0/1Six months after primary PCI

---6 (32%)15 (71%)2/3

0.065

--

0.012

-13 (68%)6 (29%)0/1Two days after primary PCI

---5 (28%)10 (50%)2/3

0.70

--

0.16

-13 (72%)10 (50%)0/1Immediately after primary PCI

MBG

0.02325.89

(18.76)-(33.02)18.88

(13.57)-(24.18)0.014

-6.2(-11.00)-(-1.39)

27.62 + 6.4621.42 + 4.98Six months after primary PCI

0.00127.51

(22.03)-(32.99)19.10

(14.16)-(24.04)<0.001

-9.27(-13.50)-(-5.03)

31.79 + 7.5822.52 + 5.58Two days after primary PCI

0.8029.36

(21.48)-(37.25)30.30

(23.14)-(37.46)0.69

-0.79(-6.66)-(5.08)

34.44 + 8.2633.6 + 9.45Immediately after primary PCI

cTFC mean

Univariate Multivariate ICSK group Control Mean diff. p ICSK group Control p

0.17

37.28(21.57-52.99)

27.84(14.35-41.32)

0.00537.05 + 13.84

(n: 18)23 + 13.37

(n: 18)Infarct size %,

SPECT

0.822.71

(-37.75)-(43.16)

5.97(-27.32)-(39.26)

0.243.46 + 19.0214.37 + 31.14Change in LVEF, %

0.2451.56

(36.90-66.23)57.68

(45.88-69.47)0.020

46.19 + 12.21 (n: 15)

56.18 + 10.69 (n: 17)

Six months after

primary PCI

0.07847.96

(39.86-56.06)54.25

(46.95-61.55)0.06

44.51 + 12.40 (n: 20)

51.52 + 10.76 (n: 21)

Two days after

primary PCILVEF %

0.03614.97

(-18.31)-(48.24)

-11.19(-37.95)-(15.58)

0.0411.90 + 23.50

(n: 15)-4.60 + 22.01

(n: 17)Change in EDV, %

0.089118.77

(76.98-160.56)92.72

(59.11-126.33)0.021

150.13 + 49.28 (n: 15)

115.70 + 29.67 (n: 17)

Six months after

primary PCI

0.50118.53

(93.35-143.71)111.22

(88.52-133.91)0.07

137.75 + 36.82 (n: 20)

119.88 + 23.36 (n: 21)

Two days after

primary PCIEDVml

0.05515.30

(-28.40)-(59.01)

-12.32(-47.47)-(-22.83)

0.01412.67 + 30.75

(n: 15)-13.27 + 25.40

(n: 17)Change in ESV %

0.06858.68

(25.10-92.27)36.08

(9.07-63.10)0.004

83.73 + 39.32 (n: 15)

50.64 + 18.23 (n: 17)

Six months after

primary PCI

0.06365.03

(47.76-82.30)50.81

(31.25-66.37)0.013

78.65 + 30.55(n: 20)

58.16 + 17.02 (n: 21)

Two days after

primary PCIESVml

p(two

tailed)

Control, mean 95%CI

ICSK (+), mean, 95%CI

p(two

tailed)ControlICSK (+)

Univariate Multivariate

Left Ventricular End Systolic (ESV) and End Diastolic Volumes (EDV), Ejection Fraction (LVEF) and Infarct Size (%) Comparisons

Comments and Conclusions

Early phase results:

• In this pilot trial, low-dose intracoronary streptokinase administration immediately following primary PCI was compared with standard primary PCI without use of intracoronary streptokinase.

• Almost all indices of microvascular perfusion concordantly pointed out that use of intracoronary streptokinase immediately after primary PCI yields better perfusion at the microvascular level.

Comments and Conclusions 2

Late term results • At six months, there was no significant difference

between the two study groups with regards to left ventricular size or function and infarct size, although there were some trends favoring the streptokinase group.

• The trial was not originally planned to be large enough to detect differences in long-term outcome, and indeed enrollment was terminated early based on the midterm data on microvascular perfusion.

• Since trends in favor of the intracoronary streptokinase group were detected, it is possible that the study was underpowered for these analyses.

Comments and Conclusions 3

• The finding of the current study supports the in situ formed (autochthonous) microvascular thrombus hypothesis and pointed out that this thrombus should be taken into consideration for achieving more efficient reperfusion at microvascular level during primary PCI.

• The results of the study should be confirmed by a larger randomized study before applying this treatment modality in daily cardiology practice.

Following NEJM Publication in 2007Following NEJM Publication in 2007

Goal of IC SK After PCI: Get the microvasculature openGoal of IC SK After PCI: Get the microvasculature open

0

5

10

15

20

25

0.30.3 0.30.3

4.64.62.82.8

9.59.5

15.615.6

10.210.2

20.220.2

P<0.002P<0.002P<0.04P<0.04

P<0.09P<0.09

P<0.0008P<0.0008

UrgentRevascularization

UrgentRevascularization

RecurrentMI

RecurrentMI

DeathDeath MACEMACE

IC Compared to IV Abciximab Reduces MACE in ACS Pts IC Compared to IV Abciximab Reduces MACE in ACS Pts

Undergoing PCIUndergoing PCI IC Compared to IV Abciximab Reduces MACE in ACS Pts IC Compared to IV Abciximab Reduces MACE in ACS Pts

Undergoing PCIUndergoing PCI

Wöhrle J et al. Circulation 2003;107:1840.Wöhrle J et al. Circulation 2003;107:1840.

N = 403 ptsIC – 294IV – 109

N = 403 ptsIC – 294IV – 109

UA and MIUA and MI

IV abciximabIV abciximabIC abciximabIC abciximab

49%49%

Clot Disaggregation Following IC Eptifibatide: Pre-PCI Angiogram

Pinto et al, Am J Cardiol 2006

Retrospective Experience with IC Eptifibatide

Pinto et al, Am J Cardiol 2006

• 59 patients treated with unbuffered IC eptifibatide:

• TIMI Grade 3 flow in >90% of patients following PCI• Normal TIMI myocardial perfusion grade 3 flow (TMPG 3) present in 54.4% of patients following PCI (range 20%-25% in past)• There were no in-hospital deaths, reinfarctions, or TIMI major bleeding events • No arrhythmias during IC eptifibatide administration

Impact of IC Adenosine on Clinical & Electrocardiographic Outcomes in the Setting Primary PTCA

Impact of IC Adenosine on Clinical & Electrocardiographic Outcomes in the Setting Primary PTCA

18

00

20

40

60

80

100

Death

18

00

20

40

60

80

100

Death

85

59

0

20

40

60

80

10085

59

0

20

40

60

80

100

% Developing Q Waves

% Developing Q Waves

48

18

0

20

40

60

80

100

48

18

0

20

40

60

80

100

% Death, MI, CHF, Recurrent Angina% Death, MI, CHF, Recurrent Angina

p < 0.02p < 0.02 p < 0.04p < 0.04p < 0.03p < 0.03

Marzilli et al, Circulation 2000; 101:2154-2159Marzilli et al, Circulation 2000; 101:2154-2159

Placebo Placebo Adenosine 4 mg in 2 ml via central lumen of PTCA balloonAdenosine 4 mg in 2 ml via central lumen of PTCA balloon

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