Master Class:
Advanced CV Risk management in cardiology
June 17-18, 2011, London
Presentation topic
Managing the acute coronary
syndrome: What is new?
Slide lecture prepared and held by:
Prof. Adam Timmis
Barts and the London School of
Medicine and Dentistry
University of London
Declining incidence of Myocardial
Infarction
Age-sex-adjusted data from Kaiser Permanente CA
Age-Sex-Adjusted Incidence of Myocardial Infarction by Year
Incidence
(per 100 000 person-years)
300
250
Any MI
200
NSTEMI
150
100
STEMI
50
0
1999
2000
2001
2002
2003
2004
Year
2005
2006
2007
2008
Potential drivers of reduced AMI rates
Rates of diabetes in patients with 1st AMI
• Life-style and risk factors?
MINAP data
↓ smoking
↑ diabetes, diagnosed hypertension,
dyslipidaemia
Outpatient
prior
to AMI
Outpatientmedication
Medication Use use
Prior to
Myocardial
Infarction
Kaiser Permanente data CA
• Medication use?
Statin
Proportion of Use (%)
↑ all preventive medication
50
40
β-Blocker
ACE-I/ARB
30
B-blocker
ACEARB
20
Thienopyridine
10
Non-Statin Lipid Lowering
0
1999
2000
2001
2002
2003
2004
2005
2006
Year
Outpatient Medication Use Prior to ST-Elevation
Myocardial Infarction
2007
2008
What about revascularisation?
PTCA vs medical: Cardiac death or myocardial infarction
Katritsis, D. G. et al. Circulation 2005
• 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
Stable angina
• CABG?
Assessment of the angiographic
severity of coronary stenosis is
inadequate to accurately predict the
time or location of a subsequent
coronary occlusion
Little et al. Circulation 1988
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 from
a) Recurrent ischaemic events
 2° prevention therapy
b) 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
Components of pre-hospital delay in STEMI
Frequency distributions using MINAP data for 2004-2005
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
BHF Doubt Kills Campaign
ended 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 from
a) Recurrent ischaemic events
 2° prevention therapy
b) Lethal arrhythmias
 implantable defibrillator
STEMI: reperfusion therapy
Primary PCI
Adjunctive Antiplatelet
Therapy
• Aspirin 300mg
• Clopidogrel 600mg
• ± Abciximab
Impact of door to balloon time
ACC-NCDR Cath PCI Registry: 2005-2006 (n=43,801)
10.3 (10.0-10.7)
2.9 (2.8-3.1)
Rathore BMJ (2010)
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
DES vs BMS for primary PCI: metaanalysis of RCTs (n=2786)
HR: 0.80 (0.48-1.39)
HR: 0.38 (0.29-0.50)
Kastrati A et al. Eur Heart J 2007;28:2706-2713
Dual antiplatelet therapy (DAPT) continue for 12 months after DES
Refining 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 rates
GRAVITAS 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-carriers
Paré G, et al. N Engl J Med 2010
New Inhibitors of the platelet
the ADP P2Y12 receptor
Receptor
Binding
Prodrug
Half life
(requires hepatic
activation)
Onset of
Action
Clopidogrel Irreversible
Yes
Slow
Long
Prasugrel
Irreversible
(stronger)
Yes
More rapid
Long
Ticagrelor
Reversible
(stronger)
No
Rapid
Short
PLATO: ticagrelor vs clopidogrel in ACS
(n=18624)
Wallentin L et al. N Engl J Med 2009
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;
NSTEMI: emergency treatment
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: don’t under-estimate it
Prognosis: poor
Probability of dying
NSTEMI
Non-MI ACS
STEMI
Undertreated
Chest Pain
?cause
100
STEMI
Days after
presentation
Treatment rate (%)
90
80
70
NSTEMI
60
50
40
30
Trop -ve ACS
20
10
0
03
Q1
03
Q2
03
Q3
03
Q4
04
Q1
04
Q2
04
Q3
04
Q4
Year and quarter
05
Q1
05
Q2
05
Q3
05
Q4
Trials of Invasive vs Conservative
Treatment Strategy in NSTEMI
O’Donoghue, M. et al. JAMA 2008;300:71-80
Routine Versus Selective Invasive Strategy in
NSTEMI
Meta-Analysis of Individual Patient Data (n=5467)
CV Death or MI
Time to 1st Revasc Procedure
Fox, K. A. A. et al. J Am Coll Cardiol 2010
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 from
a) Recurrent ischaemic events
 2° prevention therapy
b) Lethal arrhythmias
 implantable defibrillator
Adjusted KM curves: 1 yr survival by
number of 2° prevention drugs
MINAP discharge data NSTEMI and STEMI 2003-2009
0.1
1
0.08
2
0.06
0.04
3
0.02
4
0
0
180
Days after discharge from hospital
360
Impact of under-utilisation: adjusted HRs (95% CI)
for death by discharge regimens that exclude key
2° prevention drugs
MINAP discharge data NSTEMI and STEMI 2003-2009
Hazard ratio (95% CI) for death
GPRD: Continuing statin therapy in 12m
post ACS
N=6607 linked GPRD-MINAP records
Discontinuation of clopidogrel(“noncompliance”) after discharge from hospital
Linked 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 nonadherence 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 from
a) Recurrent ischaemic events
 2° prevention therapy
b) Lethal arrhythmias
 implantable defibrillator
Implantable defibrillator post
AMI
NICE 2007
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
The revolution for coronary outcomes in east London
How it was
Thrombolysis
2° prevention
1° PCI