Managing the acute coronary syndrome: What is new?

Prof. Adam TimmisBarts and the London School of

Medicine and DentistryUniversity of London

Slide lecture prepared and held by:

Master Class: Advanced CV Risk management in cardiologyJune 17-18, 2011, London

Presentation topic

Declining incidence of Myocardial InfarctionAge-sex-adjusted data from Kaiser Permanente CA

Any MI

NSTEMI

STEMI

• Life-style and risk factors?

↓ smoking

↑ diabetes, diagnosed hypertension, dyslipidaemia

0

10

20

30

40

50

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year

Prop

ortio

n of

Use

(%)

ACE-I/ARB

Thienopyridine

Non-Statin Lipid Lowering

β-Blocker

Statin

0

10

20

30

40

50

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

B-blockerACE-ARB

Outpatient medication use prior to AMI Kaiser Permanente data CA

• Medication use?

↑ all preventive medication

Rates of diabetes in patients with 1st AMIMINAP data

Potential drivers of reduced AMI rates

What about revascularisation?

• PCI?

“88% of patients believed that PCI would reduce their risk for MI, and 82% believed that it would reduce their risk for death”Rothberg MB et al. Ann Intern Med 2010

• CABG?

Assessment of the angiographic severity of coronary stenosis is inadequate to accurately predict the time or location of a subsequent coronary occlusionLittle et al. Circulation 1988

PTCA vs medical: Cardiac death or myocardial infarctionKatritsis, D. G. et al. Circulation 2005

Stable angina NSTEMI - 18/12 after RCA, LAD grafts

Summary 1.

• Rates of AMI declining

• Likely consequence of life-style and treatment factors

• Revasc non-contributory

Life Saving Strategies in AMI

1. Prevent pre-hospital death from 1° VF get the patient to a defibrillator ASAP

2. Prevent hospital death from heart failure initiate reperfusion therapy ASAP

3. Prevent late deaths froma) Recurrent ischaemic events

2° prevention therapyb) Lethal arrhythmias

implantable defibrillator

1st episode of VF/1000 pts/hr

33% of people who die from AMI do so before they reach hospital

Sayer J Heart 2002

Time to call for help accounts for most of the variation in pre-hospital delay. Culprits

• Older people (>70 yrs)• Women• People with diabetes• Pain onset in early hours• Pain at w/e

Components of pre-hospital delay in STEMI Frequency distributions using MINAP data for 2004-2005

BHF Doubt Kills Campaignended October 2007

the message!

Summary 2.

• 33% of all AMI deaths occur out-of-hospital

• Shortening the time to call for help the single most important way to save lives in AMI

• Public awareness campaigns never been shown to work

Life Saving Strategies in AMI

1. Prevent pre-hospital death from 1° VF get the patient to a defibrillator ASAP

2. Prevent hospital death from heart failure and cardiogenic shock initiate reperfusion therapy ASAP

3. Prevent late deaths froma) Recurrent ischaemic events

2° prevention therapyb) Lethal arrhythmias

implantable defibrillator

Primary PCI

STEMI: reperfusion therapy

Adjunctive AntiplateletTherapy

• Aspirin 300mg

• Clopidogrel 600mg

• ± Abciximab

Impact of door to balloon time ACC-NCDR Cath PCI Registry: 2005-2006 (n=43,801)

Rathore BMJ (2010)

2.9 (2.8-3.1)

10.3 (10.0-10.7)

Culprit only vs complete revascularisation in STEMI: meta-analysis J Thromb Thrombolysis 2011

Complete Revasc• No benefit for mortality• No benefit for recurrent MI• Reduced need for repeat revasc

Kastrati A et al. Eur Heart J 2007;28:2706-2713

DES vs BMS for primary PCI: meta-analysis of RCTs (n=2786)

HR: 0.38 (0.29-0.50)HR: 0.80 (0.48-1.39)

Dual antiplatelet therapy (DAPT) - continue for 12 months after DESRefining aspirin/clopidogrel treatment regimens to protect against late thrombosis

• Prolonged DAPT for >12 months

No effect on 2 yr event rates Park S-J et al. N Engl J Med 2010

• Titrate clopidogrel dose against platelet function testing

No effect on 6 month event ratesGRAVITAS Investigators. JAMA 2011

• Adjust clopidogrel dose according to genotype

Clopidogrel prodrug activated in liver by cytochrome P-450 (CYP) enzymes

Carriers of loss-of-function CYP alleles have same event rates as non-carriersParé G, et al. N Engl J Med 2010

New Inhibitors of the platelet the ADP P2Y12 receptor

Receptor Binding

Prodrug (requires hepatic activation)

Onset of Action

Half life

Clopidogrel Irreversible Yes Slow Long

Prasugrel Irreversible (stronger)

Yes More rapid Long

Ticagrelor Reversible (stronger)

No Rapid Short

Wallentin L et al. N Engl J Med 2009

PLATO: ticagrelor vs clopidogrel in ACS(n=18624)

Reduced risk of CV events with no increase in bleeding risk

1° PCI: 1 year mortality by baseline CRP and adjunctive treatment with abciximab or placebo.Pooled analysis of 4 ISAAR trials (n=4847)

Iijima R et al. Heart 2009;

PCI: moderate high risk

1. Aspirin + clopidogrel ± GP IIb/IIIa inhibitor

2. LMWH - now fondaparinux (factor Xa inhibitor)

3. Anti-ischaemic drugs (BB, nitrates)

4. ± Angiography ± PCI

NSTEMI: emergency treatment

NSTEMI

Non-MI ACS

STEMI

Chest Pain ?cause

Days after presentation

Pro

bab

ility

of

dyi

ng

0

10

20

30

40

50

60

70

80

90

100

03Q1

03Q2

03Q3

03Q4

04Q1

04Q2

04Q3

04Q4

05Q1

05Q2

05Q3

05Q4

Year and quarter

Trea

tmen

t rat

e (%

)

STEMI

NSTEMI

Trop -ve ACS

NSTEMI: don’t under-estimate it

Prognosis: poor

Undertreated

Trials of Invasive vs Conservative Treatment Strategy in NSTEMI

O’Donoghue, M. et al. JAMA 2008;300:71-80

Fox, K. A. A. et al. J Am Coll Cardiol 2010

Routine Versus Selective Invasive Strategy in NSTEMIMeta-Analysis of Individual Patient Data (n=5467)

CV Death or MI Time to 1st Revasc Procedure

Life Saving Strategies in AMI

1. Prevent pre-hospital death from 1° VF get the patient to a defibrillator ASAP

2. Prevent hospital death from heart failure and cardiogenic shock initiate reperfusion therapy ASAP

3. Prevent late deaths froma) Recurrent ischaemic events

2° prevention therapyb) Lethal arrhythmias

implantable defibrillator

Adjusted KM curves: 1 yr survival by number of 2° prevention drugsMINAP discharge data NSTEMI and STEMI 2003-2009

0 180 360

Days after discharge from hospital

0

0.02

0.1

0.04

0.06

0.08

1

2

3

4

Impact of under-utilisation: adjusted HRs (95% CI) for death by discharge regimens that exclude key 2° prevention drugsMINAP discharge data NSTEMI and STEMI 2003-2009

Hazard ratio (95% CI) for death

GPRD: Continuing statin therapy in 12m post ACSN=6607 linked GPRD-MINAP records

Discontinuation of clopidogrel(“non-compliance”) after discharge from hospitalLinked MINAP-GPRD registries (n=8445)

• Median Duration of therapy: 12m

• Hazard of death/AMI

– clopidogrel vs no clopidogrel HR 0.57 (0.50-0.65)

– discontinuation vs continuation HR 2.62 (2.17-3.17)

Summary 4.

• 2° prevention therapy - additive beneficial effects on survival

• diminishing efficacy probably caused by non-adherence to treatment in primary care

• non-adherence to clopidogrel in linked GPRD-MINAP registries more than doubles the risk of recurrent myocardial infarction or death during the first year.

Life Saving Strategies in AMI

1. Prevent pre-hospital death from 1° VF get the patient to a defibrillator ASAP

2. Prevent hospital death from heart failure and cardiogenic shock initiate reperfusion therapy ASAP

3. Prevent late deaths froma) Recurrent ischaemic events

2° prevention therapyb) Lethal arrhythmias

implantable defibrillator

2° prevention• Late cardiac arrest VT/VF• Sustained VT with syncope• Sustained VT and LV ejection fraction <35%

1° prevention • AMI >4 weeks previously • LV ejection fraction <30% and QRS >120msec• LV ejection fraction <35% and non-sustained VT

on Holter

Implantable defibrillator post AMINICE 2007

How it was

Thrombolysis

2° prevention

1° PCI

The revolution for coronary outcomes in east London