Trial Vignettes 1-3

Mark MasonHarefield Hospital

Royal Brompton and Harefield NHS Trust

MY CONFLICTSOF INTEREST ARE

Research grant from Medtronic

EXPORT AMI

• 1ry objective: evaluate flow improvement in pts with AMI within 12 hours of Sx onset undergoing conventional stenting or 1ry aspiration with Export catheter followed by stenting

EXPORT AMI

Primary aspiration (n=120) Conventional stenting (n=129)

AMI within 12 hrs

EXPORT AMI

• Primary endpoint: rates of ST resolution >50% (60 minutes post-procedure) and/or Blush grade III; why?

• In AMI, TIMI III restored in 94% but normal perfusion in only 28%– Blush 0: no blush– Blush 1: blush but no clearance– Blush 2: blush which clears minimally or not at all

in 3 cardiac cycles– Blush 3: blush washes out and clears in 3 cycles

EXPORT AMI

Primary aspiration (n=120) Conventional stenting (n=129)

AMI within 12 hrs

1ry endpoint (%) 85 71.9 0.025

No reflow (%) 3.3 10.1 0.04

TIMI frame count 22.82 20.86 0.02

‘Bailout’ (rescue IIb/IIIa)(%)5.8 14.7 0.02

MACCE @ 30 days(%) 5.8 4.7 0.675

p

EXPORT AMI• Conclusions

– Restoration of TIMI III flow does not necessarily prevent infarction

– Use of Export aspiration device appears safe

– Routine use of Export device appears associated with

improvements in surrogates of microvascular reperfusion

(disappointing that there is no attempt to evaluate final infarct

size- ?underpowered)

– No difference in MACCE at 30 days

HORIZONS AMI

3000 pts

1 : 3

UFH + IIb/IIIa(n=1802)

Bivalirudin +/- provisional IIb/IIIa(n=1800)

BMS Taxus

PCI CABG Medical Rx

Angio

>3400 pts with STEMI and Sx onset <12 hrs

•Assessed at 30 days, 6 months and 1-5 years•Primary objectives:

–Bivalirudin offers equivalence or reduction in composite of MACE and major bleeding–Bivalirudin offers equivalence or reduction in major bleeding

•Includes all-comers inc. LMS and shock

HORIZONS AMI

• 30 day results (stent randomisation still blinded):

• F/U available for 1778 UFH arm vs. 1777 Bivalirudin

UFH + GP IIb/IIIa InhibitorN=1802

Bivalirudin Monotherapy

N=1800Primary PCI Deferred PCI CABG Medical Rx

HORIZONS AMI

Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99RR = 0.99 [0.76, 1.30]

PPsupsup = 1.00 = 1.00

Diff = Diff = -3.3% [-5.0, -1.6] RR = RR = 0.60 [0.46, 0.77]

PPNINI ≤ 0.0001 ≤ 0.0001PPsupsup ≤ 0.0001 ≤ 0.0001

Diff = Diff = -2.9% [-4.9, -0.8]RR = RR = 0.76 [0.63, 0.92]

PPNINI ≤ 0.0001 ≤ 0.0001PPsupsup = 0.006 = 0.006

1 endpoint 1 endpoint

*Not related to CABG*Not related to CABG**MACE = All cause death, reinfarction, ischemic TVR or stroke**MACE = All cause death, reinfarction, ischemic TVR or stroke

Overall mortality at 30 days 3.1% UFH vs. 2.1% Bivalirudin, p=0.048

30 day Stent Thrombosis30 day Stent ThrombosisUFH + UFH +

GP IIb/IIIaGP IIb/IIIa(N=1553)(N=1553)

BivalirudinBivalirudin(N=1571)(N=1571)

PPValueValue

ARC definite or probable* 1.9%1.9% 2.5%2.5% 0.330.33

- definite 1.4%1.4% 2.2%2.2% 0.110.11

- probable 0.5%0.5% 0.3%0.3% 0.260.26

- acute (≤24 hrs) 0.3%0.3% 1.3%1.3% 0.00090.0009

- subacute (>24 hrs – 30d) 1.7%1.7% 1.2%1.2% 0.300.30

*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated

HORIZONS AMI

Conclusions– There appears to be a clear treatment difference

at 30 days– This appears to be exclusively due to a reduction

in bleeding complications– There does appear to be a lower mortality with

bivalirudin at 30 daysBUT– There is a significantly higher incidence of acute

stent thrombosis

AMIHOT II (!) AMIHOT I

– 269 pts with anterior or large inferior MI, TIMI < 2, undergoing primary or rescue PCI within 24 hours of symptoms

– I/C supersaturated O2 post-PCI for 90 minutes No overall difference in infarct size, ST resolution,

improvement in regional wall motion

BUT Anterior infarcts reperfused within 6 hours had reduced

infarct size, higher incidence of complete ST resolution and more improvement in regional wall motion

AMIHOT II

Anterior MI reperfused by stenting within 6 hours TIMI < 2 at presentation Two primary endpoints:

– Efficacy- infarct size (superiority) by SPECT sestamibi at 14 days

– Safety- 30 day MACE (non-inferiority)

‘Bayesian hierarchical modelling’ allowed for pooling of data from AMIHOT I and II (!)

AMIHOT II

2.8:1 randomisation

SSO2222

(SPECT 209)

Control79

(SPECT 72)

304 pts enrolled(3 randomisation errors)

301 by ITT

•No difference in primary endpoints in AMIHOT II•No difference in proportion with ‘0%’ infarcts

HOWEVER………

AMIHOT II When AMIHOT I and II pooled: Infarct size reduced (p=0.023) Higher proportion of ‘0%’ LV infarcts (18.3% SSO2

vs. 10.3%, p=0.03) No difference in MACE

– 4.7% all pts/3.8% AMIHOT II + ant MI < 6hrs AMIHOT IVs.

5.9%/5.5% respectively, p= 0.57/0.48

AMIHOT II Observations:

– AMIHOT II was a negative study– Questionable clinical validity of pooling data in

this way– Study groups chosen at opposite extremes-

– < 6 hours includes pts who would do well anyway– Up to 24 hours will include pts who will not do well

regardless– SPECT data might be more useful if ‘acute’ and

‘convalescent’ scan performed Conclusions:

– This evidence does not suggest any clinically useful myocardial salvage