急性心肌梗塞的溶栓治療課件

Combination

Lytic

Therapy

inAcute

Myocardial

InfarctionC.

Michael

Gibson,

M.D.Pathophysiology

of

Combination

Therapy

in

AMI*Gibson

et

al.J

Am

Coll

Cardiol.

1995;25:582-589.Gibson

et

al.Circulation.

2001;103:2550-2554.Combination

Therapy↓

Thrombus↓

%

Stenosis↑

Minimum

Diameter↑

Epicardial

Flow↑

MyocardialFlowFacilitates

PCIReducesReinfarction*↑

Myocardial

Blush↑

ST

ResolutionRecent

Clinical

TrialsTrialLyticGPIIb/IIIaReceptor

InhibitorAnticoagulantGUSTO-V100%r-PA50%

r-PANoneAbciximabStandard-dose

heparinLow-dose

heparinASSENT-3100%TNK-tPA50%

TNK-tPA100%TNK-tPANoneAbciximabNoneACC/AHA

heparin

doseLow-dose

heparinEnoxaparinENTIRE50%

TNK-tPA50%

TNK-tPA100%TNK-tPA100%TNK-tPAAbciximabAbciximabNoneNoneUnfractionated

heparinEnoxaparinUnfractionated

heparinEnoxaparinClinical

Trials:

OngoingINTEGRITILow-dose

heparinLow-dose

heparinLow-dose

heparinLow-dose

heparinLow-dose

heparinLow-dose

heparinTirofibanTirofibanTirofibanEptifibatideEptifibatideEptifibatide50%

TNK-tPA75%

TNK-tPA100%TNK-tPA50%

TNK-tPA75%

TNK-tPA100%TNK-tPAFASTERAnticoagulantGPIIb/IIIaReceptor

InhibitorLyticTrial54%32%GUSTO-I:

A

20%

Increase

in

TIMI

Grade

3

Flow

isNeeded

to

Yield

a

1%

Mortality

ReductionThe

GUSTO

Angiographic

Investigators.

N

Engl

J

Med.

1993;329:1615-1622.5060403020%

TIMI

Grade

3

Flowt-PASK100t-PA57.4%6.3%SK876TIMI

Grade

3

Flow

–

Pooled

Data

From

DoseConfirmation

Phases

of

Recent

Trials040801006020%

Patients

With

TIMI

Grade

3

FlowGUSTO-I90

min547370474056787354566429263

58T14

t-PA90

min87

88T14

r-PA90

min98

100SPEED60-90

min81

75INTRO-AMI60

min329

321Pooled60-90

minLytic

aloneCombinationSPEED:

Results

of

Dose-Confirmation

PhaseThere

was

a

7.4%improvement

in

the

rateof

TIMI

Grade

3

flowIf

a

20%improvementis

required

to

improvemortality

by

1%,

then

a7.4%

improvement

wouldbe

predicted

to

improvemortality

by0.3%The

SPEED

Study

Group.

Circulation.

2000;101:2788-2794.04080100r-PA

10+10

Ur-PA

5+5

U

+

Abx6020Patency

(%)TIMI-2TIMI-3n=109n=11521.654.947.528.7GUSTO-V:

Study

DesignST

↑,

lytic

eligible,

<

6

h(n=16,588)ASANoAbciximab2

x

10

U

bolus(30’)Full-dose

r-PAAbciximabLow-dose

Heparin:60

U/kg

bolus

followed

by7

U/kg/h

infusion1o

end

point:

mortality

at

30

days2o

end

point:

clinical

and

safety

events

at

30daysTheGUSTO-VInvestigators.

Lancet.

2001;357:1905-1914.2

x

5

U

bolus

(30’)Half-dose

r-PAStandard

Heparin:5000

U

bolus

followed

by800

U/h

(<

80

kg)

or1000

U/h

(≥

80

kg)infusionPrimary

End

Point:

30-Day

Mortality%

MortalityDaysTheGUSTO-VInvestigators.

Lancet.

2001;357:1905-1914.0051030P=.43

for

superiorityNon-Inferiority

RR0.95(95%CI,

0.84-1.08)Std.

Reteplase

(n

=

8260)Abx

+

↓

Dose

Reteplase

(n

=8328)15

20

254625.9%5.6%GUSTO-V:

NoninferiorityAnalysisAdapted

with

permission

from

the

GUSTO-V

Investigators.

Lancet.2001;357:1905-1914.Non-Inferiority

RR

0.95(95%CI,

0.84-1.08)OR

and

95%

CI0.02.01.0Abciximab

+Half-dose

r-PA

superiorFull-dose

r-PAsuperiorUpper

Boundary

of

95%

CI

for

Noninferiority1.11A

Comparison

of

the

Outcomes

With

r-PAMonotherapy

in

GUSTO-IIIvs

GUSTO-V

TrialsThe

GUSTO-IIIInvestigators.

NEnglJMed.

1997;337:1118-1123.TheGUSTO-VInvestigators.

Lancet.

2001;357:1905-1914.0378512647.4%5.9%10,1388,260GUSTOIII GUSTO

VDeathP<.0010405020301048%37%10,1388,260GUSTOIII GUSTO

VAnteriorMI1.00.9GUSTOIIIGUSTO

V0.91%0.59%10,1388,260ICHP=.0150.80.70.60.50.40.30.20.101.21.72.3GUSTO-V:

Causes

of

Reinfarction*Unblinded,

unadjudicatedTheGUSTO-VInvestigators.

Lancet.

2001;357:1905-1914.01342Myocardial

Infarction

(%)Any

Q-waveEnzymaticIschemic

STChange*0.50.21.62.7r-PAr-PA

+AbxP<.00013.5Non-Intracranial

Bleeding

Through

Discharge/Day

7TheGUSTO-VInvestigators.

Lancet.

2001;357:1905-1914.0%

of

Patients15253020r-PAr-PA

+Abx10SevereBleedingModerateBleedingMildBleedingAnyBleedingReceivingTransfusions100.51.11.83.511.420.013.724.64.05.7ICH

by

AgeGroup*Significant

treatment

interaction

for

the

age

75

dichotomy;P=.033.TheGUSTO-VInvestigators.

Lancet.

2001;357:1905-1914.0132%

of

Patients≤

75

yrs0.41.20.51.10.4r-PA(n=8260)r-PA

+

Abx

(n=8328)0.3P=.66P=.531.5P=.27*P=.069*2.112/1088

24/114975

yrs28/717937/717225/2030

31/213570

yrs24/6230

21/6193≤

70

yrs****GUSTO-V:

PCI

Within

6

Hours

(Urgent)and

Through

Day

7*P<.0001.TheGUSTO-VInvestigators.

Lancet.

2001;357:1905-1914.5.625.427.98.61530252010PCI

(%)UrgentThrough

Day

750r-PAr-PA

+Abx2.89.05.4GUSTO-V:

Event

Rates

in

Those

Requiring

Urgent

PCI6.74.89.6410128Myocardial

Infarction

(%)r-PAr-PA

+Abxn=117320Death Repeat

MI Death

Plus

RepeatMIHeartwire

News.

September

2,

2001.

GUSTO-V:

Combination

half-dose

fibrinolytic

plus

IIb/IIIa

blocker.

An

Alternativeapproach

toMI?6GUSTO-V:

ConclusionsCompared

with

r-PA

monotherapy,

combination

therapy

withr-PA

and

abciximab

resulted

inA

mortality

rate

that

was

not

inferior

to

r-PA

monotherapyFewer

nonfatal

reinfarctions

(primarily

a

reduced

incidenceof

recurrent

ST

elevation)A

lower

rate

of

urgent

revascularizationMore

noncerebral

bleeding

complications,

transfusions,and

thrombocytopeniaA

higher

rate

of

ICH

in

elderly

patients

over

the

age

of75yearsASSENT-3:

Rationale

for

Use

of

EnoxaparinTNK-tPA

plus

enoxaparin–

Favorable

effects

of

LMWHs

in

recent

small-scalethrombolysis

trialsHART-2HART-2ASSENT-PlusHigher

late

patency: ASSENT-Plus AMI-SKLess

reocclusion:Fewer

reinfarctions: AMI-SKWilson,

et

al.ASSENT-3

is

the

first

large-scale

trial

to

test

LMWHASSENT-3:

Study

DesignST-Segment

Elevation

AMI

(n=6095

patients)150

to

325

mg

ASA(daily)RandomizedFull-dose

TNK-tPAPlus

EnoxaparinHalf-dose

TNK-tPAPlus

AbciximabPlusLow-dose

HeparinFull-dose

TNK-tPAPlus

Weight-adjusted

UFHThe

ASSENT-3Investigators.

Lancet.

2001;358:605-613.ASSENT-3:

Primary

End

PointsPrimary

Efficacy

End

Point:Composite

of

30-day

mortality

orin-hospital

reinfarction

or

in-hospital

refractory

ischemia.Primary

Efficacy

Plus

Safety

End

Point:

Composite

of

30-daymortality

or

in-hospital

reinfarction

or

in-hospital

refractoryischemia

plus

in-hospital

intracranial

haemorrhage

or

in-hospitalmajor

bleeding

other

than

intracranial.ASSENT-3:

30-Day

Mortality,

Recurrent

MI,Refractory

Ischemia10501520%

Risk

of

30-Day

D/MI/Ref

IschTNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH*P-values

are

the

Bonferroni

P-values

after

correcting

for

multiple

comparisons.

The

uncorrected

P-values

were

P=.0002for

the

enox

vs

UFH

comparison,

and

P<.0001

for

the

abx

vs

UFHcomparison.11.411.115.43-wayP=.0001P=.0002*P=.0009*ASSENT-3:

30-Day

Mortality,

Recurrent

MI,Refractory

Ischemia,

Major

Bleeding

and

ICH%

Risk

of30-Day

D/MI/Ref

Isch/Maj

Bleed/ICH*P-values

are

the

Bonferroni

P-values

after

correcting

for

multiple

comparisons.

The

uncorrected

P-values

were

P=.0037for

the

enox

vs

UFH

comparison,

and

P=.0142

for

the

abx

vs

UFHcomparison.10501520TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH13.814.217.03-wayP=.0062P=.0057*P=.0146*Kaplan-Meier

CurvesUFHAbx*30201816141210864200Enox*log-rank

P=.0001*vsUFH5

10

15

20

25Days

to

death,

reinfarction,

orrefractory

ischemiaPrimary

Efficacy

End

PointProbability

(%)Reprinted

with

permission

from

the

ASSENT-3

Investigators.

Lancet.

2001;358:605-613.3020181614121086420log-rank

P=.0062*vs

UFH

+

Abx0

5

10

15

20

25Days

to

death,

reinfarction,

refractoryischemia,

ICH,

or

major

bleedingPrimary

Efficacy

PlusSafety

End

PointProbability

(%)UFHAbxEnox*ASSENT-3:

Primary

Efficacy

and

Safety

End

Point

ofDeath,

Reinfarction

or

Refractory

Ischemia,

ICH

or

MajorBleeding

in

Patients

>75

Years

of

Age*There

was

a

statistically

significant

interaction

between

treatment

with

abciximab

and

age

such

that

patients

over

theage

of

75

had

poorer

outcomes

with

abciximab

(P=.001).%

Risk

of30-Day

Efficacyand

Safety

End

PointTNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH25.528.0P=.001*36.9454035302520151050ASSENT-3:

Primary

Efficacy

and

Safety

End

Point

ofDeath,

Reinfarction

or

Refractory

Ischemia,

ICH

or

MajorBleeding

in

Patients

with

Diabetes*There

was

a

statistically

significant

interaction

between

treatment

with

abciximab

and

diabetes,

such

that

diabeticshadpoorer

outcomes

with

abciximab

therapy

(P=.0007).%

Risk

of30-Day

Efficacyand

Safety

End

Point152530TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH13.922.316.5P=.007*201050ASSENT-3:

30-Day

Mortality810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH5.46.66.03-wayP=.256420%

Risk

of30-Day

MortalityASSENT-3:30-DayDeathorMI%

Risk

of30-Day

Death

or

MI810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH7.39.13-wayP=.01986.86420ASSENT-3:

In-Hospital

Recurrent

MI%

Risk

of

In-HospitalRecurrent

MI45TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH2.72.24.23-wayP=.00093210ASSENT-3:

In-Hospital

Refractory

Ischemia%

Risk

of

30-DayRefractory

Ischemia4810TNK-tPA+EnoxTNK-tPA+AbxTNK-tPA+UFH3.26.53-wayP<.000164.620ASSENT-3:

Incidence

of

In-Hospital

Thrombocytopeniaand

Noncerebral

Bleeding

Complications*While

3-way

P-value

is

significant,

Enox

vs

UFH

comparison

P=NSAny

thrombocytopeniaEnox(n=2040)1.2Abx(n=2017)3.2UFH(n=2038)1.3P-Value3-way<.0001Thrombocytopenia<20,000

cells/μL0.10.50.2<.000120,000

to

50,000

cells/μL0.20.60.250,000

to

<100,000

cells/μL0.92.01.0Bleeding

episodesTotal25.6*39.721.1<.0001Major3.0*4.32.2.0005Minor22.6*35.418.8<.0001Blood

transfusion3.4*4.22.3

.0032ASSENT-3:In-Hospital

Stroke

Rates*Including

hemorrhagic

conversionEnoxAbxUFH(n=2040)(n=2017)(n=2038)P-ValueTotal

strokes1.621.491.520.94Intracranial

hemorrhage0.880.940.930.98Ischemic

stroke*0.640.400.540.57Hemorrhagic

conversion0.070.070.000.77Unclassified0.150.150.050.59Patients

Undergoing

PCI:

MortalityASSENT-3:

In-Hospital

PCIGUSTO-V:

UrgentPCI57863Mortality

(%)42102.53.72.75.46.7TNK-tPA

+EnoxTNK-tPA

+AbxTNK-tPA

+UFHr-PA+UFHr-PA+AbxHow

Does

Actual

Weight

ComparetoEstimated

Weight?Reprinted

with

permission

from

Cannon

CP,

et

al.J

Am

Coll

Cardiol.

2001;37:323A.40.536.4Actual

Patient

Weight

(kg)Estimated

Patient

Weight

(kg)Correlation

Between

Estimated

and

Actual

Patient

Weight

in

TIMI

10B188.5R2=0.93,

P<.0001181Weight-Based

Dosing

of

Thrombolysis:

How

Well

Do

WeEstimate

Weight?

How

Often

Would

This

Translate

IntoErrors

With

Administration

of

Thrombolytic

Drugs

andAdverse

Outcomes?Errors

in

estimating

weight

are

uncommon,

especiallythose

that

would

lead

to

a

dose

change

(1.3%

or

49/3730for

TNK-tPA

and

4.5%

or

13/290

fort-PA).No

adverse

outcomes

were

seen

among

patients

whoreceived

an

incorrect

dose,

suggesting

a

broad

safetyprofile

for

the

new

single-bolus

agentTNK-tPA.Cannon

CP,

et

al.

J

Am

Coll

Cardiol.2001;37:323A.ASSENT-3:

Study

Group

Conclusions

RegardingTNK-tPA

+

Abciximab

Therapy“The

results

obtained

with

half-dose

tenecteplase

plus

abciximab

arevery

similar

to

those

withhalf-dose

reteplase

and

abciximab

seen

inGUSTO-V.”“In

both

trials,

these

benefits

are

obtained

at

the

cost

of

a

higher

rateof

major

bleeding

complications

and

blood

transfusions.”“No

benefit

and

perhaps

even

harm

was

observed

in

patients

above75

years

and

indiabetics.”“Taken

together

they

suggest

that

caution

should

be

exercised

regardingthe

use

of

conjunctive

therapy

with

abciximab

in

elderly

patients

with

anacute

myocardial

infarction

treated

with

a

fibrinolytic

agent.”The

ASSENT-3Investigators.

Lancet.

2001;358:605-613.ASSENT-3:

Study

Group

Conclusions

RegardingEnoxaparin“In

view

of

the

present

data

and

the

ease

of

administration,enoxaparin

might

be

considered

an

attractive

alternativeanticoagulant

treatment

when

given

in

combination

withtenecteplase.”The

ASSENT-3Investigators.

Lancet.

2001;358:605-613.ENTIRE

TIMI-23:

Study

DesignUFH60

U/kg

bolus12

U/kg/h

infusion≥

36

hENOXvarying

doses+/-

IV