“Adjunctive Therapy”Non ST segment elevation ACS

Dr M R ThomasDr M R Thomas

King’s College Hospital.King’s College Hospital.

Advanced Angioplasty 2002Advanced Angioplasty 2002

Plaque Rupture

Unstable angina

Non ST elevationAMI

ST elevationAMI

“Adjunctive Therapy”Non ST segment elevation ACS

Pre-PCI (assume DGH admission)Pre-PCI (assume DGH admission)

Peri-PCIPeri-PCI

Post PCIPost PCI

UK Perspective!!UK Perspective!!

“Adjunctive Therapy”Non ST segment elevation ACS

Pre PCIObvious medical therapy.Obvious medical therapy.

- aspirin.- aspirin.

- anti-anginals.- anti-anginals.

- lipid lowering.- lipid lowering. MIRACL:MIRACL:

80mg atorvastatin v placebo80mg atorvastatin v placebo

Un angina/non Q MIUn angina/non Q MI

Rx for 16 weeksRx for 16 weeks

Primary endpoint: death, non fatal Primary endpoint: death, non fatal MI,cardiac arrest and emergency MI,cardiac arrest and emergency re-hospitalisationre-hospitalisation

13.5

14

14.5

15

15.5

16

16.5

17

17.5

1ary endpoint

Placebo

Atorvastatin

MIRACL TRIAL

P=0.048

Is there a need for Is there a need for revascularisation?revascularisation?

And therefore generally And therefore generally transfer to a tertiary centre.transfer to a tertiary centre.

Cons v Invasive Strategies 4 randomised clinical trials

TIMI IIIB VANQWISH FRISC-2 TACTICS

Years 1989-92 1993-94 1996-98 1998-2000

Patients 1473 920 2457 2220

UA/NSTEMI 68%/32% 0%/100% 41%/59% 62%/38%

Meds ASA/UFH ASA/UFH ASA/Dalteparin

ASA,UFH,Tirofiban

GP IIb/IIIa 0% 0% 10% 100%

Stents 0% 0% 60% 85%

High surgical mortality.7.7% overall and 12% inthe invasive arm

Median time to angiography 4 daysMedian time to revascularisation 4 (PCI) to 7 (CABG)

Median time to angiography 22 hrsMedian time to revasc 25 (PCI) to 89 (CABG) hrs

“Adjunctive Therapy”Non ST segment elevation ACS

So assuming some or all patients will need revasularisation (PCI) what is the best type

and combination of drugs pre PCI

Heparin, UFH or LMWHHeparin, UFH or LMWH IIb/IIIa receptor inhibitorsIIb/IIIa receptor inhibitorsClopidogrelClopidogrel

Heparin: LMWH or UFH

Essence and TIMI 11BEssence and TIMI 11B

These trials have These trials have demonstrated an advantage demonstrated an advantage of LMWH over UFH in UA of LMWH over UFH in UA and other trials have shown and other trials have shown at least equivalence.at least equivalence.

Also ease of use compared to Also ease of use compared to UFH.UFH.

Worries about combination Worries about combination

with IIb/IIIa now resolved.with IIb/IIIa now resolved.

Incidence of death/MI in patients at 1 year: effects of enoxaparin more marked in PCI

patients, TIMI 11B/ESSENCE meta-analysis

17.7

11.6

16.6

12.5 12.411.5

02468

1012141618

% patients

PCI ontreatment

PCI inhospital

ALLdeath/MI

UFHEnoxaparin

OR (95% CI)0.61 (0.35,1.06)

OR (95% CI)0.72(0.49,1.04)

OR (95% CI)0.92(0.81,1.04)

IIb/IIIa receptor inhibitors““National Institute of Clinical Excellence” National Institute of Clinical Excellence”

Guidance on the use of glycoprotein IIb/IIIa inhibitors Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. in the treatment of acute coronary syndromes.

September 2000September 2000

(1) For high risk patients with unstable angina or non-Q MI, the (1) For high risk patients with unstable angina or non-Q MI, the intravenous use of GP IIb/IIIa inhibitors in addition to low intravenous use of GP IIb/IIIa inhibitors in addition to low (adjusted) dose UFH is recommended.(adjusted) dose UFH is recommended.

(2) In unstable angina, raised blood levels of troponin should be used (2) In unstable angina, raised blood levels of troponin should be used to identify those at high risk.to identify those at high risk.

NB: Pre GUSTO IV ACS

In the absence of revascularisation In the absence of revascularisation value of IIb/IIIa receptor inhibitors value of IIb/IIIa receptor inhibitors “small” and evidence favours small “small” and evidence favours small

molecules.molecules.

CURECURE (OASIS-4)Clopidogrel in Unstable

Angina to preventRecurrent ischemic

Events

Months of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.0

20

.04

0.0

60

.08

0.1

00

.12

0.1

4

0 3 6 9 12

Cumulative Hazard Rates for CV Death/MI/Stroke

P < 0.001

Clopidogrel

Placebo

Cum

ulat

ive

Haz

ard

Rat

es

Months of Follow-up0 3 6 9 12

6303

6259

5780

5866

4664

4779

3600

3644

2388

2418

Plac

Clop

No of Pts

9.3%

11.4%20% RRcp 20% Prism + 6/129.6% Pursuit 30 days

Transfer for revascularisation.

Does everyone need to be Does everyone need to be transferred for angiography and transferred for angiography and

possible revascularisation?possible revascularisation?

Risk stratification

Baseline ST segment change

Recurrent Ischaemia

Value of Baseline CPK-MB in ACS (PURSUIT)

1.92.9

4.55.1

6.2

8

0

12

34

56

78

9

0-1 >2-3

>5-10

30 daymortality(%)

10.99.9

6.98.1

5.5

4

0

2

4

6

8

10

12

0-1 >1-2 >2-3 >3-5 >5-10

>10

8 monthmortality (%)

Prognostic value of Baseline Troponins

Gusto IIA: 30 day mortality (%)

3.9

11.8

0

2

4

6

8

10

12

30 day mortality

Trop T negTrop T pos

P<0.001

TACTICS-TIMI 18: Stratified by Troponin T

3.1 2.9

10.6

5.3

0

2

4

6

8

10

12

Trop T<0.01 Trop T>0.01

ConservativeInvasive

OR=0.95p=NS

OR=0.47p=0.002

Low risk patients

Data supports an ischaemia-guided Data supports an ischaemia-guided approach with treadmill exercise or approach with treadmill exercise or pharmacological stress.pharmacological stress.

Transfer!

So we have transferred the high risk patient:So we have transferred the high risk patient:

- troponin +, recurrent ischaemia, ST depression.- troponin +, recurrent ischaemia, ST depression.

ONON

- aspirin, LMWH, clopidogrel, IIb/IIIa in ideal - aspirin, LMWH, clopidogrel, IIb/IIIa in ideal world!! (24 hrs)world!! (24 hrs)

BUTBUT

in UK aspirin, LMWH and clopidogrel (2 in UK aspirin, LMWH and clopidogrel (2 weeks!)weeks!)

Transfer

Is there a problem with LMWH Is there a problem with LMWH and IIb/IIIa?and IIb/IIIa?

“Acute II”

First randomised trial of IIb/IIIa blockers First randomised trial of IIb/IIIa blockers and LMWH in ACS.and LMWH in ACS.

525 ACS patients on aspirin and Tirofiban 525 ACS patients on aspirin and Tirofiban (Aggrastat).(Aggrastat).

Randomised to LMWH (enoxaparin) or Randomised to LMWH (enoxaparin) or UFH.UFH.

Primary endpoint: SAFETY.Primary endpoint: SAFETY.

Safety endpoints in Acute-2

Endpoint Tirofiban plus LMWH Tirofiban plus UFH

Any Bleed 4.7% 5.2%

Major bleed 0.6% 0.5%

Cutaneous bleed 19.4% 21%

Transfusion 2.2% 2.9%

Thrombocytopenia 0.3% 0.5%

30 day event rates in ACUTE II

Event Tirofiban plusLMWH

Tirofiban plusUFH

P value

Death 2.2% 2.4%

MI 7.0% 7.6%

Stroke 0.3% 1.4%

Re-hosp for UA 2.5% 6.6% 0.026

Revascularisation 12.1% 18.1% 0.058

Paragon-B appears to similar results for Lamifiban

International Task ForceRecommendations (Feb 2001)

(Karl Karsch from UK)

no additionalUFH or LM W H

+/- G P IIb/IIIa

cath w ithin <8h of last SC dose

enoxaparin 0.3 m g/kgiv bolus

UFH 50 U/kgACT 200-250s

+ G P IIb/IIIa

enoxaparin 0.3 m g/kgiv bolus

UFH 60 U/kgACT 250-300s

- GP IIb/IIIa

cath w ithin 8-12 h of last SC dose

UA/NST EM ILM W H initiated

IIb/IIIa receptor inhibitors

Which patients…….all or defined by Which patients…….all or defined by coronary anatomy?coronary anatomy?

Which compound………?any Which compound………?any

Delivered when………?upstream or after Delivered when………?upstream or after diagnostic angiogram.diagnostic angiogram.

“Adjunctive Therapy”Non ST segment elevation ACS

Post Discharge

2ary prevention, lipids etc2ary prevention, lipids etc AspirinAspirin ClopidogrelClopidogrel

PCI-A prospective, randomized, double-A prospective, randomized, double-

blind substudy of patients blind substudy of patients undergoing PCI in the CURE trialundergoing PCI in the CURE trial

0.02

0.04

0.06

0.08

5 10 15 20 25 30

Clopidogrel

Placebo

0.0

RR 0.7095% CI 0.50-0.97P=0.03

Days following PCI

Cu

mu

lati

ve H

aza

rd R

ate

Primary Endpoint: CV Death, MI, Urgent Revascularization

Mehta SR et al. Lancet 2001:358:527-33

0 100 200 300 400

0.0

0.02

0.04

0.06

0.08

0.10

Clopidogrel

Placebo

RR 0.7595% CI 0.56-1.00P=0.047

Days following PCI

Cu

mu

lati

ve H

aza

rd R

ate

CV Death, MI:From PCI to End of Followup

Mehta SR et al. Lancet 2001:358:527-33

CV Death or MI at Various Intervals

12.6

5.14.4

3.93.12.9

3.6

8.8

0

2

4

6

8

10

12

14

Overall BeforePCI

PCI to30 d.

30 d. to1 yr

CV

de

ath

or

MI (

%)

PlaceboClopidogrel

RRR 31% 32% 34% 21%

*

*P=0.002 Mehta SR et al. Lancet 2001:358:527-33

Guidelines

““Guidelines for the management of patients Guidelines for the management of patients with acute coronary syndromes without with acute coronary syndromes without persistent ECG ST elevation”persistent ECG ST elevation”

Heart 2001;85:133-142Heart 2001;85:133-142

We live in the UKQuestions

Where should diagnostic angiography be performed?Where should diagnostic angiography be performed?

Where should interventional cardiology be Where should interventional cardiology be performed?performed?

Who should perform interventional procedures?Who should perform interventional procedures?

How do we increase the availability of both of the How do we increase the availability of both of the above? above?

ALL OF THE ABOVE IS AS/MORE ALL OF THE ABOVE IS AS/MORE IMPORTANT AS THE DATA!IMPORTANT AS THE DATA!

ConclusionsI think we know the data:I think we know the data:aspirin, lipid lowering, clopidogrel, LMWH, risk aspirin, lipid lowering, clopidogrel, LMWH, risk

assessment and IIb/IIIa with early revascularisation assessment and IIb/IIIa with early revascularisation in the high risk group.in the high risk group.

Providing an optimal service in the UK Providing an optimal service in the UK via the NHS…….now that’s a via the NHS…….now that’s a different story!!different story!!