intracoronary streptokinase a fter primary percutaneous coronary intervention *

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

*N Engl J Med 2007;356:1823-34.

http://www.istanbul.edu/index.php

Rational of the studyFrom Epicardial Coronaries…

• Primary percutaneous coronary intervention (PCI) is the most effective reperfusion method in the treatment of STEMI.

• Nevertheless, processes causing myocardial damage are not immediately terminated despite elimination of epicardial occlusion with successful primary PCI.

• It has been presumed that mechanisms of reperfusion injury including embolization of epicardial thrombus and plaque content to microvasculature are responsible for this ongoing damage.

• Unfortunately, almost all of the previous studies based on these hypothesis and aiming to stop reperfusion injury have not been succeeded.


… to the Microvasculature

• There is a growing evidence pointing concordance between myocardial and microvascular damage in STEMI patients.

• Microvascular damage might not be only an accompanying process to the myocardial damage. Also there might be a causal relationship in between.

• If one focused to microvasculature during peri-PCI procedure, it can be easily realized that another and important contributor might have a role in this process.

insitu microvascular thrombus!


Virchow’s Triad and Autochthonous Thrombus

• All three components of Virchow’s triad (blood constituent, endothelial damage and stasis) exist at extreme levels in the microvasculature of infarcted myocardium.

• Therefore, in situ (de-novo) formed fraction may constitute the main part of the thrombus located in infarct site’s microvasculature.

Virchow RR. Cellular Pathology. London, Churchill, 1860.


Coronary Vascular Resistance

• If epicardial and microvascular vessels are considered as serially connected resistances, elimination of the proximal epicardial occlusion and retrieval of whole epicardial thrombus would not be enough to normalize total coronary resistance and perfusion at affected segments.


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

g m

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


Study Endpoints

Primary endpoints:• Coronary flow reserve, • Index of microvascular resistance, • Coronary wedge pressure, • Collateral flow index, and• Coronary diastolic deceleration time were primary endpoints.

Secondary endpoints: • Corrected TIMI frame count, • Myocardial blush grade, • Infarct size, • Changes in left ventricular volumes and• Major adverse cardiac events (reinfarction, revascularization and death) were secondary endpoints.


Statistical Analysis• Calculations were then made of the necessary sample size to detect

a 30% difference between the intracoronary streptokinase and control groups for each end point (α=0.05, β=0.20, power=0.80).

• Group proportions were compared by means of the chi-square test or Fisher exact test, as appropriate. Group means were compared by Student’s t test for independent groups or the Mann-Whitney U test, for variables with normal or non-normal distribution, respectively

• Group means were also adjusted for possible confounding factors (age, pain-to-balloon time, diabetes, hypertension, hyperlipidemia, pre-myocardial infarction angina, slow flow, side branch embolization, smoking and infarct location) using analysis of covariance (ANCOVA).


Results


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)

p(two tailed)

Control Groupn: 20

Intracoronary Streptokinase Group n: 21

Study Group Baseline and Demographic Characteristics.


Concomitant medications during primary PCI and in the Coronary Care Unit

Intracoronary Streptokinase

Group n: 21

Control Group

n: 20

p

(two tailed)

Aspirin 21 (100%) 20 (100%) 1

Beta- Blocker 19 (90%) 18 (90%) 0.96

LMWH 21 (100%) 20 (100%) 1

GP IIb/IIIa inhibitor 21 (100%) 20 (100%) 1

Clopidogrel 21 (100%) 20 (100%) 1

Statins 19 (90%) 18 (90%) 0.96

IV nitroglycerin 16 (76%) 12 (60%) 0.44

ACE inhibitor 19 (90%) 16 (80%) 0.61


Angiographic Characteristics

ICSK groupControl group

p

Infarct related artery

LAD 14 (67%) 16 (80%)

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

Cx 1 (5%) 1 (5%)

Number of diseased vessels

1 16 (76%) 14 (70%)

0.732 4 (19%) 4 (20%)

3 1 (5%) 2 (10%)

Baseline TIMI flow 0/1 (%) 100 100 1

Pain to balloon time (minute) 257.7 ± 211.8 218.8 ± 109,8 0.93


-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


Invasive Microvascular Parameters Two Days after PCI

Index of Microvascular Resistance

11.73

29.05

0

5

10

15

20

25

30

ICSK Group Control Group

Un

its

p<0.001

n : 21 n : 20



Coronary Flow Reserve

2,29

1,66

0,00

0,50

1,00

1,50

2,00

2,50


p : 0.002

(un

itle

ss)

n : 21 n : 20



Coronary Wedge Pressures (Mean and Systolic)

7,98

15,1712,54

29,46

0,00

5,00

10,00

15,00

20,00

25,00

30,00


p : 0.04p : 0.04

p < 0.001

mm

Hg

n : 21 n : 20



Pressure Derived Coronary Flow Index

0,08

0,17

0,00

0,02

0,04

0,06

0,08

0,10

0,12

0,14

0,16

0,18


p : 0.002

(un

itle

ss)

n : 21 n : 20


Intracoronary Hemodynamic Indices of Microvascular Perfusion

Univariate Multivariate

IntracoronaryStreptokinase

Groupn:21

ControlGroupn:20

MeanDifference 95%

CI

p

IntracoronaryStreptokinase

Group, Mean

(95% CI)

ControlGroup,Mean

(95% CI)p

IMR (U) 16.29 + 5.06 32.49 +11.04-16.20

(-21.75)(10.64)<0.001

11.73

(5.53)-(17.92)

29.05

(22.17)-(35.92)<0.001

CFR 2.01 + 0.57 1.39 + 0.310.62

(0.35)-(0.93)<0.001

2.29

(1.92)-(2.66)

1.66

(1.25)-(2.07)0.002

CWP, mean (mmHg)

10.81 + 5.46 17.20 + 7.93-6.39

(-10.73)-(-2.05)0.004

7.98

(2.84)-(13.12)

12.54

(6.83)-(18.24)0.04

CWP, systolic (mmHg)

18.24 + 6.07 33.80 + 11.0-15.56

(-21.27)-(-9.85)<0.001

15.17

(8.26)-(22.08)

29.46

(21.80)-(37.12)<0.001

CFIp (mean, unitless)

0.08 + 0.05 0.17 + 0.07-0.09

(-- 0.13)-(-0.06)<0.001

0.08

(0.05)-(0.11)

0.17

(0.14)-(0.21)0.002


Relatively Less Invasive Microvascular Parameters Immediately, Two Days, and Six Months after PCI

Corrected TIMI Frame Count

30,30

19,1 18,88

29,3627,51

25,89

0,00

5,00

10,00

15,00

20,00

25,00

30,00

35,00


p : 0,80p : 0,80 p : 0,001 p : 0,023

Fra

me/

seco

nd

n : 21 n : 20n : 21 n : 20n : 21 n : 20n : 21 n : 20n : 19 n : 18n : 19 n : 18


Non-invasive Microvascular Parameters Two Days after PCI

Diastolic Desceleration Time (in LAD pts)

750

257

0

100

200

300

400

500

600

700

800


p : 0,001

mil

lise

con

ds

n : 21 n : 20


ST Segment ResolutionImmImmeediatelydiately and 60 Minutes after PCI

66,75

77,26

71,36 71,05

60,00

62,00

64,00

66,00

68,00

70,00

72,00

74,00

76,00

78,00


p : 0,45p : 0,45p : 0,39

%

n : 21 n : 20n : 21 n : 20


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 mean+SD mean+SD mean and 95%CI mean and 95%CI


Echocardiographic Volumes at Two DaysTwo Days and Six Months after PCI

End-Systolic Volumes

50,81

36,08

65,0858,68

0,00

10,00

20,00

30,00

40,00

50,00

60,00

70,00


p : 0,063p : 0,063p : 0,068

ml

n : 21 n : 20n : 19 n : 18



End-Diastolic Volumes

111,22

97,72

118,53 118,77

0,00

20,00

40,00

60,00

80,00

100,00

120,00


p : 0,50p : 0,50p : 0,089

ml



LV Ejection Fraction

54,2557,68

47,9651,56

0,00

10,00

20,00

30,00

40,00

50,00

60,00


p : 0,078 p : 0,078 p : 0,24

%


Infarct Size Six Monts after PCI

27,84

37,28

0,00

5,00

10,00

15,00

20,00

25,00

30,00

35,00

40,00


p : 0,17p : 0,17

%

n : 18 n : 18


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 PCI

LVEF %

0.03614.97

(-18.31)-(48.24)-11.19

(-37.95)-(15.58)0.04

11.90 + 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)


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)


EDVml

0.05515.30

(-28.40)-(59.01)-12.32

(-47.47)-(-22.83)0.014

12.67 + 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)


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)


ESVml

p(two tailed)

Control, mean 95%CI

ICSK (+), mean, 95%CI

p(two tailed)

ControlICSK (+)

U n i v a r i a t e M u l t i v a r i a t e

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.


intracoronary streptokinase a fter primary percutaneous coronary intervention *

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