Download - Simon Redwood KCL St Thomas’ Hospital
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Simon RedwoodKCL
St Thomas’ Hospital
ST Elevation ACS
Adjunctive Therapy
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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
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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)
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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
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RAPPORT
ReoPro in AMI; Primary PCI Organization and Randomized Trial
Circulation 1998; 98:734-41
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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)
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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
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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
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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
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Trials of Stenting versus PTCA
•PAMI-STENT: NEJM 1999; 341: 1949-56
•CADILLAC: JACC 2001; 37 (Suppl. A): 343A and TCT 2000; Oral presentation
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PAMI-STENT
Primary Angioplasty in Myocardial Infarction STENT
NEJM 1999; 341: 1949-56
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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
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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
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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
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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
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CADILLAC
Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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Trials of Stent and Abciximab versus Stent alone
• ISAR-2: JACC 2000; 35: 915-21
•ADMIRAL: NEJM 2001; 344: 1895-903
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ISAR-2
Intracoronary Stenting and Antithrombotic Regimen
JACC 2000: 35:915-21
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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
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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
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ADMIRAL
Abciximab Before Direct Angioplasty and Stenting in
Myocardial Infarction Regarding Acute and Long Term Follow-up
NEJM 2001; 341:1895-1903
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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
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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
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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
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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
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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
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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
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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
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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
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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