Managing the acute coronary syndrome: What is new? Prof. Adam Timmis Barts and the London School of Medicine and Dentistry University of London Slide lecture prepared and held by: Master Class: Advanced CV Risk management in cardiology June 17-18, 2011, London Presentation topic

Declining incidence of Myocardial Infarction Age-sex-adjusted data from Kaiser Permanente CA Any MI NSTEMI STEMI

Life-style and risk factors? ↓ smoking ↑ diabetes, diagnosed hypertension, dyslipidaemia B-blocker ACE- ARB Outpatient medication use prior to AMI Kaiser Permanente data CA Medication use? ↑ all preventive medication Rates of diabetes in patients with 1st AMI MINAP 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 occlusion Little et al. Circulation 1988 PTCA vs medical: Cardiac death or myocardial infarction Katritsis, 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 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

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

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

Primary PCI STEMI: reperfusion therapy Adjunctive Antiplatelet Therapy Aspirin 300mg Clopidogrel 600mg ± Abciximab

Impact of door to balloon time ACC-NCDR Cath PCI Registry: (n=43,801) Rathore BMJ (2010) 2.9 ( ) 10.3 ( )

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: DES vs BMS for primary PCI: meta- analysis of RCTs (n=2786) HR: 0.38 ( ) HR: 0.80 ( )

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 (requires hepatic activation) Onset of Action Half life Clopidogrel IrreversibleYesSlowLong Prasugrel Irreversible (stronger) YesMore rapidLong Ticagrelor Reversible (stronger) NoRapidShort

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 Probability of dying 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 NSTEMI Meta-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 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 Days after discharge from hospital

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 Hazard ratio (95% CI) for death

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

Discontinuation of clopidogrel(“non- compliance”) 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 ( ) – discontinuation vs continuation HR 2.62 ( )

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 from a)Recurrent ischaemic events  2° prevention therapy b)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 120msec LV ejection fraction <35% and non-sustained VT on Holter Implantable defibrillator post AMI NICE 2007

How it was Thrombolysis 2° prevention 1° PCI The revolution for coronary outcomes in east London