Simon RedwoodKCL

St Thomas’ Hospital

ST Elevation ACS

Adjunctive Therapy

Trials of Abciximab and PTCA versus PTCA

•EPIC Post-Hoc Analysis - AMI subgroup: Am J Cardiol 1996; 77: 1045-51

•RAPPORT: Circulation 1998; 98: 734-41

00 1 2 3 4 5 6

10

20

30

40

50

% o

f P

atie

nts

EPIC - Post-Hoc Analysis - AMI Subgroup

Months

Death, MI or TVR through 6 Months

adapted from AJC 1996; 77:1045-51

Placebo (n = 23)

Abciximab Bolus Only (n = 19)

Abciximab Bolus + Infusion (n = 22)

91%p = 0.002

47.8%

4.5%

32.3%

64 patients

(of 2099)

EPIC - Post-Hoc Analysis - AMI subgroup

•Post-Hoc analysis indicates that Abciximab offers profound and robust benefit in primary PCI compared to primary PCI alone

•Based on these results prospective trials were designed to evaluate the efficacy of Abciximab in Primary PCI (RAPPORT trial)

Conclusions

RAPPORT

ReoPro in AMI; Primary PCI Organization and Randomized Trial

Circulation 1998; 98:734-41

RAPPORT - Study Design

AMI < 12 hours; candidates for 1° PTCAn = 483 patients from 36 centres between 11/95 and 2/97

Randomised on a double-blind basis

Placebo100 U/kg UFH

Maintain ACT > 300s

Abciximab (B + I)*100 U/kg UFH

Maintain ACT > 300s

Circulation 1998; 98:734-41

1° Endpoint: D/MI/TVR through 6 months2° Enpoints D/MI/Urgent TVR through 7 and 30 days

* 0.25 mg/kg bolus with 0.125 g/kg/min infusion (max 10 g/min)

RAPPORT - Primary Endpoint

Event Rates through 6 months - Intention to Treat

28.1

17.8

28.2

11.6

0

10

20

30

40

50

% o

f P

atie

nts

p = 0.90

n = 242 n = 241

p = 0.048

Circulation 1998; 98:734-41

n = 242 n = 241

Placebo

Abciximab

Death/MI/Any TVR1 Death/MI/Urgent TVR2

1 Primary Endpoint; 2 Secondary Endpoint

RAPPORT - Secondary Endpoints

Event Rates through 30 Days - Intention to Treat

12.0

5.87.9

4.6 4.61.8

0

5

10

15

20

25

% o

f P

atie

nts

p = 0.004

n = 242 n = 241

p = 0.006

Circulation 1998; 98:734-41

Placebo

Abciximab

n = 242 n = 241 n = 242 n = 241

p = 0.52

Death/MI/Urgent TVR Re-MI Urgent TVR*

* TVR within 24 hrs for severe recurrent ischaemia

RAPPORT

• Abciximab given during primary PTCA for MI did not alter the primary endpoint at 6 months which included elective revascularisation procedures

• Abciximab given during primary PTCA for MI did decrease death / reinfarction / urgent revascularisation at day 7, 30 and 6 months

• Abciximab reduced the need for bailout stenting• 20.4% vs 11.9%, p = 0.008, 42% reduction

• Abciximab + primary PTCA shows better efficacy than primary PTCA alone

Conclusions

Trials of Stenting versus PTCA

•PAMI-STENT: NEJM 1999; 341: 1949-56

•CADILLAC: JACC 2001; 37 (Suppl. A): 343A and TCT 2000; Oral presentation

PAMI-STENT

Primary Angioplasty in Myocardial Infarction STENT

NEJM 1999; 341: 1949-56

PAMI-STENT

Study design

Randomised, multicentre900 patients with acute myocardial infarction undergoing

emergency catheterisation and angioplasty

Angioplasty alone(n = 448)

6-months composite endpointDeath/Re-MI/disabling stroke/TVR

Angioplasty with stenting* (n = 452)

NEJM 1999; 341: 1949-56

* Heparin coated PS153

PAMI-STENT

0

5

10

15

20

25

30 PTCA Stent + PTCA

Death Incidence of Angina

% o

f p

atie

nts

6-months results

20.1

12.6

2.74.2

16.9

11.3

p < 0.01

p = 0.27

p = 0.02

Death/Re-MI / disabling stroke/TVR

0.054 3.0% 5.4%Mortality (12 months)

0.0460.04692.7%92.7% 89.5%89.5%TIMI-3 flow final (core lab)TIMI-3 flow final (core lab)

0.020.0296.4%96.4% 92.9%92.9%TIMI-3 flow final (operator)TIMI-3 flow final (operator)

NSNS 4.5%4.5% 5.8%5.8%AbciximabAbciximab

Heparin coated PS-153Heparin coated PS-153StentStent

<0.0001<0.000121.0%21.0% 10.6%10.6%Ischaemic TVR (6 months)Ischaemic TVR (6 months)

<0.0001<0.000135.4%35.4% 23.5%23.5%Angio. restenosis (6.5 mos)Angio. restenosis (6.5 mos)

448448452452nn

p-valuep-valuePTCAPTCAStentStent

PAMI-STENT

PAMI-STENTConclusions• Implantation of a stent for acute myocardial infarction has

clinical benefits beyond those of primary coronary angioplasty alone (decreased restenosis and TVR)

• Despite improvements in ischaemic and restenotic endpoints, stented patients had a non significant trend for higher mortality after one year versus PTCA alone (5.4% vs 3.0%, p =0.054)

• But: longer time to presentation (120 vs 110 mins p = 0.03)bulky PS 153low abciximab use

• Stent shows better efficacy than PTCA, although the mortality is questionable

CADILLAC

Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications

Protocol Schematic (open label)

12 month clinical follow-up7 month follow-up angiographic subset

Primary PTCA+

No abciximab

MultiLink stent+

No abciximab

MultiLink stent+

Abciximab

Primary PTCA+

Abciximab

Primary endpoint - 6 month composite incidence of death, reinfarction, disabling stroke, or ischaemic TVR

Acute myocardial infarction

CADILLAC - Place/Time of Administration

No Pre-Catheterisation Abciximab

The lesion may be crossed with the guidewire prior to the abciximab bolus;PTCA should be performed as soon as the bolus is complete and prior to the start of the infusion.

CADILLAC - Baseline Characteristics

TCT 2000; Oral Presentation

Variable

Age (Median, yrs)

range

Male(%)

Diabetes (%)

Hypertension (%)

Hyperlipidemia (%)

Current Smoker (%)

Family History (%)

PTCANo Abx

(n = 516)60

22-90

71.4

15.4

43.1

35.5

41.7

30.8

PTCAAbx

(n = 529)61

29-91

73.8

16.7

50.4

40.0

43.3

33.2

StentNo Abx

(n = 512)60

28-96

72.4

16.2

48.3

36.8

44.8

30.7

StentAbx

(n = 525)61

24-94

74.1

19.3

44.1

36.8

44.4

31.7

p = NS for all

10.8*

19.3

15.2

10.9

0

5

10

15

20

25

Death, re-MI, Ischaemic TVR or Disabling Stroke

% o

f P

atie

nts

Primary Endpoint-MACE through 6 Months

PTCA alone PTCA + Abx Stent + AbxStent alone

p = 0.001no p value

given

* not a pre-specified primary

endpoint component

TCT 2000; Oral Presentation

4.3

1.60.8

14.2

2.3 2.10.8

2.81.2 1.2

3.82.3 1.7

5.0

12.1

7.4

0

5

10

15

20

% o

f P

atie

nts

* p = 0.002 vs. stent alone

Endpoint Components Through 6 Months

PTCA alone PTCA + Abx Stent + AbxStent alone

Disabling Stroke

Ischaemic TVRReinfacrtion

p < 0.0001

p = 0.12

*

Death

p = 0.043

1.7

0.6

1.0

0.0

1.0

2.0

Inci

den

ce

(%

)

30 Day Subacute Thrombosis

PTCA alone PTCA + Abx Stent + AbxStent alone

0.0

p = 0.07

P=0.03

All stent + abciximab comparisonsare post-hoc

CADILLAC – Core Lab Results

TCT 2000; Oral Presentation

Variable

Ref Diameter

MLD

Diameter stenosis (%)

TIMI Flow

TIMI 0/1

TIMI 3

PTCANo Abx

(n = 516)

2.98

2.17

26.6

1.0

94.9

PTCAAbx

(n = 529)

2.97

2.13

26.9

1.6

96.1

StentNo Abx

(n = 512)

2.98

2.34*

20.7*

1.6

93.8

StentAbx

(n = 525)

3.00

2.37*

20.0*

1.4

96.1

* p < 0.01 vs PTCA

QCA

Conclusions• Similar to PAMI-STENT, stents resulted in a marked

improvement in EFS compared to PCTA alone patients

• Unlike PAMI-STENT, stents DID NOT result in decreased TIMI-3 flow or survival compared to PTCA

• In patients undergoing PTCA, abciximab was associated with reduced mortality and improved EFS

• However, no major long-term clinical benefits of abciximab were seen in patients undergoing routine stenting

CADILLAC - Potential Problems

• Crossover to ReoPro in placebo arm

9.1% with PTCA, 6.1% with stent

• Low overall incidence of events (Ref 2.5-4mm, 3mm less than stent length, no tortuosity or marked Ca2+ )

• Definition of (re-) MI

• ReoPro not blinded

• Primary endpoints were: Stent vs PTCA (no ReoPro), and Stent vs PTCA (with ReoPro), NOT ReoPro vs Placebo

• More diabetics in ReoPro and stent arms

Trials of Stent and Abciximab versus Stent alone

• ISAR-2: JACC 2000; 35: 915-21

•ADMIRAL: NEJM 2001; 344: 1895-903

ISAR-2

Intracoronary Stenting and Antithrombotic Regimen

JACC 2000: 35:915-21

Clinical Outcomes through 30 days

Abciximab0.25 mg/kg bolus

followed by a continuous infusion of10 g/min for 12 hours

+Additional 2,500 U of

intra-arterial UFH* (n = 201)

Usual CareAdditional 10,000 U of

intra-arterial UFH+

1,000 U/hr for the 1st 12hours post-sheath removal*

(n = 200)

AMI within 48 hours with planned stent placement;Prior to Cath: UFH 5,000 U and 500 mg IV ASA

1:1 Randomisation

ISAR - II - Study Design

JACC 2000: 35:915-21

ISAR II - Outcomes through 30 Days

10.5

6.04.5

1.5

5.05.02.5 2.0

0.53.0

0

5

10

15

20

25

% o

f P

atie

nts

p = 0.038

p = 0.3

Usual Care (n = 200)

Abciximab (n = 201)

p = 0.16

Death, MI orAny TVR

Death TVR

52%

40% 55%p = 0.08

58%

p = 0.62 66%

Death or MI MI

JACC 2000: 35:915-21

ADMIRAL

Abciximab Before Direct Angioplasty and Stenting in

Myocardial Infarction Regarding Acute and Long Term Follow-up

NEJM 2001; 341:1895-1903

4 co

ron

ary

ang

iog

ram

s

ADMIRAL - Trial Schematic (n = 300)ST , < 12 h

ASA

Placebo + Stent Abciximab* + Stent

1º endpoint: Death, re-MI or urgent TVR through 30 days

2º endpoint: Death, re-MI or any revasc. through 30 days and 6 months

UFH70 U/kg (max. 7,000 U) followed by 7 U/kg/hr

(maintain aPTT between 1.5-2.0 X control value) until the 24 hour follow-up angiogram completed

Ticlopidine(250 mg; twice daily for 30 days post PCI)

Admission

Post-PCI

24 h Post-PCI

6 m Post-PCINEJM 2001; 341:1895-1903

ADMIRAL - Demographics

0.14

0.09

0.22

0.31

0.55

0.08

0.28

0.04

p-value

Male (kg)

Age (years)

Hx of Hypertension (%)

Diabetes (%)

Cardiogenic Shock* (%)

Hx of Heart Failure (%)

Prior CABG (%)

Prior PTCA (%)

Abciximabn = 149

85.2

59.6

34.2

15.4

7.4

2.0

10.0

18.1

14.1

Placebon = 151

78.2

62.1

41.1

19.9

9.3

0.0

13.3

10.0

7.3 0.06Hx of MI (%)

* during first 24h post randomization NEJM 2001; 341:1895-1903

ADMIRAL - Place/Time of Administration

26

73

0

20

40

60

80

100

178

266238

0

50

100

150

200

250

300

350

% o

f P

atie

nts

Tim

e b

etw

een

sym

pto

m

on

set

and

stu

dy

dru

g (

min

) p = 0.002p = 0.02

n = 78 n = 222MICU/A&E

ITU/Cath Lab

Place of Study Rx Admin. Time to Study Rx

NEJM 2001; 341:1895-1903

MICU A&E ITU/Cath Lab

ADMIRAL - Angiographic Analysis

5.410.8

16.825.8

0

20

40

60

80

100

% o

f P

atie

nts

p = 0.01

p = 0.006

TIMI 3 Flow TIMI 2/3 Flow

TIMI 3 Flow Prior To PCI

NEJM 2001; 341:1895-1903

86.792.6

82.8

95.1 95.9 94.3

p = 0.04 p = 0.33 p = 0.04

TIMI 3 Flow Post PCI

ImmediatelyPost-PCI

24 hourPost-PCI

6 monthPost-PCI

Abciximab

Placebo

ADMIRAL - 1° Endpoint through 30 days

NEJM 2001; 341:1895-1903

Death, re-MI or Urgent TVR

0 10 20 300

4

8

12

16

6.0

14.6

Placebo

Abciximab

59%p = 0.01

Days

% o

f P

ati

en

ts

ADMIRAL – Components of Primary Endpoint

0.01

0.42

0.19

p-value

Composite

Reinfarction

Death

Abciximabn = 149

6.0

1.3

3.4

1.3

Placebon = 151

14.6

2.6

6.6

6.6 0.02Urgent TVR

NEJM 2001; 341:1895-1903

ADMIRAL - 1° Endpoint through 6 Months

NEJM 2001; 341:1895-1903

Death, re-MI or Urgent TVR

15.9

7.4

0

4

8

12

16

0 50 100 150 200

53%p = 0.02

Days

% o

f P

ati

en

ts

Placebo

Abciximab

30 Day Composite EndpointDeath, MI or Urgent TVRDeath, MI or Urgent TVR

11.2 10.5

15.3

7.15.8

5.0

7.3

5.0

0

5

10

15

20

RAPPORT(n=483)

ISAR-2(n=401)

ADMIRAL(n=300)

CADILLAC*(n=2082)

Incid

en

ce (

%)

Placebo ReoPro

51%p=0.03

53%p=0.04

52%p=0.02

30%p=0.04

RAPPORT Circ 1998; 98: 735, ISAR-2 JACC 2000; 35:915, ADMIRAL Montalescot ESC 99, CADILLAC Stone TCT 2000

* includes ischaemic stroke

Abciximab + Primary PTCA is better than Primary PTCA alone

Stent is better than Primary PTCA with or without Abciximab

Abciximab + Stent is better than stent alone

Conlusions