ACUTE CORONARY SYNDROMES

Roby Rakhit BSc MD FRCP

Consultant Cardiologist Royal Free hospital

Honorary Senior Lecturer, UCL

Advanced Medicine, Manchester, 20th June 2016

Age- and Sex-Adjusted Incidence Rates of

Acute Myocardial Infarction, 1999 to 2008,

n=46,086 Yeh RW et al. N Engl J Med 2010;362:2155-2165

Incidence of ACS US & UK

Fig 1 Age standardised event rates of acute

myocardial infarction by sex and type of event,

2002-10, England n=840,175

Kate Smolina et al. BMJ 2012;344:bmj.d8059

Fig 2 Age standardised 30 day overall and case fatality rates for admissions to hospital (%) for acute

myocardial infarction by sex, 2002-10, England.

Kate Smolina et al. BMJ 2012;344:bmj.d8059

Prognosis after ACS UK

STEMI prognosis in the era of PPCI…

Unadjusted 30-day mortality 2011-2014:

•8.1% overall (n= 72,688)

•7.2% (n= 63,408) patients admitted directly to ‘primary PCI interventional centre’

•14.3% (n= 9,261) patients admitted to ‘primary PCI non-interventional centre ’

Universal definition of myocardial infarction (Thygesen K Circ 2012:16;2020-35

• Myocardial infarction should be used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischaemia. Under these conditions any one of the following criteria meets the diagnosis of myocardial infarction:

• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL) together with myocardial ischaemia with at least one of the following

– Symptoms of ischaemia

– ECG changes of new ischaemia (new ST-T changes or new LBBB)

– Development of pathological Q waves on the ECG

– Imaging evidence of loss of viable myocardium or new regional wall motion abnormality

Cardiac Troponins • Components of myocardial contractile apparatus encoded

by distinct genes

• Not detectable in healthy subjects

• Highly specific immunoassays

• False positives: PE, myocarditis, LVF, renal failure

• Troponin I (Antman et al, n=1404)

42 day mortality > 0.4ng/ml 3.7%

< 0.4ng/ml 1.0%

• Troponin T (GUSTO IIA, n=855)

30 day mortality > 0.1ng/ml 11.8%

< 0.1ng/ml 3.9%

• Troponin T (FRISC, n=437)

5 month mortality 0.2 ng/ml 13%

0.2 -0.06 ng/ml 9%

< 0.06 ng/ml 5%

Implications of Hs Troponin assays

• Higher negative predictive value for MI

• Earlier detection of MI

• Increase in detection of MI and reduction in diagnosis of unstable angina

• >90% PPV for detection of MI if 5 fold increase

• 50-60% PPV for MI if 3 fold increase

• > 99th percentile differs between hsTropT and I

– hsTropT >14 ng/L

– hsTrop I >24 ng/L

• hsTrop I male >34

• HsTrop I female >16

0 h/3 h rule-out algorithm of non-ST-elevation acute coronary syndromes

using high-sensitivity cardiac troponin assays.

Authors/Task Force Members et al. Eur Heart J

2015;eurheartj.ehv320

0 h/1 h rule-in and rule-out algorithms using high-sensitivity cardiac troponins (hs-cTn) assays

in patients presenting with suspected non-ST-elevation myocardial infarction (NSTEMI) to the

emergency department. 0 h and 1 h refer to the time from first blood test.

Authors/Task Force Members et al. Eur Heart J

2015;eurheartj.ehv320

Acute Coronary syndromes

Unstable Angina NSTEACS STEMI

NSTEMI (Trop +) 75% 25%

- ST elevation

+ persistent ST elevation

ECG changes in NSTEACS:

ST depression Evidence of previous Q wave MI

normal LBBB

Transient ST elevation T wave inversion

Minor non-specific changes

Pathophysiology • Plaque rupture/erosion/calcified nodule (Virmani JACC 2006)

• Platelet adhesion

• Thrombus formation ---> coronary occlusion

(1) Transient, intermittent and non-occlusive = UNSTABLE ANGINA

(2) Shortlasting, partly occlusive, spontaneous reperfusion = NSTEMI

(3) Prolonged and occlusive = STEMI

NON-ST ELEVATION ACS = NSTEACS = NSTEMI/UNSTABLE ANGINA

Natural History of NSTEACS

• NSTEACS precedes 50% of STEMI/ sudden cardiac death

• During first 30 days:

– Risk of death or STEMI is 10 % (GUSTO II)

– An additional 35 - 50% will experience recurrent ischaemia despite medical therapy (FRISC, TIMI IIIB, Klein)

References:

Savonitto et al. JAMA. 1999;281:707.

Days from randomization

Mort

alit

y (

%)

180 0 20 40 60 80 100 160 0

6

8

10

2

4

120 140

% mortality at six months

T-wave inversion

3.4% (n=2,723)

ST-segment elevation

& depression

9.1% (n=1,769)

ST-segment depression

8.9% (n=4,263)

ST-segment elevation

6.8% (n=3,369)

Not all NSTEACS are the same… NSTEACS with ST depression has a 30% higher mortality at 6 months than STEMI (GUSTO IIb)

ECG: RBBB and “posterior” ST depression

GRACE – Global Registry of Acute Coronary

Events. Eagle KA, Lim MJ, Dabbous OH, et al. JAMA 2004;291:272–733.

• Multi-national registry of patients admitted with ACS at 94 hospitals in 14 countries (70,359 enrolled)

• Includes UA,STEMI,NSTEMI.

• The primary endpoint was all-cause mortality within 6 months of discharge.

• Nine predictors for the 6-month mortality were derived.

• Age per 10 year increase above 40.

• History of MI

• History of CHF

• Tachycardia

• Hypotension

• Elevated Creatinine.

• Elevated Cardiac Enzymes.

• ST depression

• Absence of in hospital PCI.

Predicted 6-month mortality Risk of future adverse cardiovascular events

1.5% or below Lowest

> 1.5 to 3.0% Low

> 3.0 to 6.0% Intermediate

> 6.0 to 9.0% High

over 9.0% Highest

Risk categories derived from Myocardial Ischaemia National Audit Project (MINAP) database

Very High Risk < 2hours

Mechanical complications of MI

Recurrent ST/T changes

Acute HF

High Risk < 24 hours

Positive Troponin

Recurrent ST/T changes

GRACE score >140

Intermediate Risk < 72 hours

Diabetes

CKD (eGFR <60)

EF <40% or congestive HF

Prior PCI or CABG

Early post MI angina

GRACE score >109 and <140

Low Risk

Any characteristics not mentioned above

Timing of angiography: current clinical guidelines

NICE 2014 ESC 2015

• 3031 patients randomised early <24hrs vs delayed <36hrs angiography (GRACE)

• Primary endpoint composite: death, new MI, stroke at 6 months

• Secondary end point: composite death, MI, refractory ischaemia, stroke, re-intervention at 6 months

TIMACS trial May 2009 N Engl J Med 2009;360:2165-75.

Mehta SR, et al. N Engl J Med. 2009;360:2165-75.

High risk defined as GRACE risk >140

How are we doing?

Current pathway for NSTEACS for patients presenting to hospitals with angiogram only facilities

Facilitating access for high risk NSTEACS

Koganti & Rakhit BMJ Open in press

NSTEACS KEY MESSAGES

• Risk assessment (GRACE) is important in all NSTEACS presentation

• High risk NSTEACS with ST depression has a greater risk compared with ST elevation alone

• hsTrop assays allow rapid rule out of ACS using either 3 hr or 1 hr algorithms

• Angiography should be offered within 24 hours for patients at high clinical risk and <72 hours for intermediate risk patients

ST ELEVATION MI = STEMI

STEMI THE TRAINCRASH....

“Time Is Muscle” The Wavefront of Necrosis

CM Gibson 2002

Acute Inferior MI

Meta-analysis of 23 randomised trials 7739 patients: 4-6 week data Keeley EC, Boura JA, Grines CL The Lancet 2003;361:13-20

0%

2%

4%

6%

8%

10%

12%

14%

Death Exc.Shock Non-fatal MI CVA Combined

PCI

Lysis

P=0.0002 P=0.0003 P<0.0001 P=0.0004 P<0.0001

Association of door-to-balloon time and mortality in patients admitted to hospital with ST elevation myocardial infarction: national cohort study Rathore SS BMJ 2009

ACC national CVD registry 2005-2006 n=43801

120min

Fig. 3. Log-rank analysis showing better survival in the HAC group.

ST–Segment-Elevation Myocardial Infarction Patients

Randomized to a Pharmaco-Invasive Strategy or Primary

Percutaneous Coronary Intervention (STREAM)

Sinnaeve P et al 2014 Circulation 130(14):1139-1145 Copyright © American Heart Association, Inc. All rights reserved.

1:1 randomisation Immediate PCI vs Tenecteplase and then PCI (if PCI not deliverable within 60min)

Do I treat culprit only or culprit and bystander disease in STEMI?

14% reduction cardiac death,MI, repeat revascularisation

50% reduction cardiac death,MI, repeat revascularisation

STEMI KEY MESSAGES

• PPCI, ideally direct access to a HAC, is the gold standard treatment for STEMI and should be delivered within 120min of symptom onset

• If PPCI cannot be timely delivered facilitation with fibrinolytic therapy and PCI after is an alternative

• Radial access is preferred to femoral

• Complete revascularisation should be performed either at the time of PCI or as a in-hospital staged procedure

ANTI-THROMBOTIC MEDICATION

Mechanism of platelet activation and site of action of platelet inhibitors

Story R Heart 2011

Agent Class Mode Onset Offset/ withdrawbefore surgery

Dose Caution Trials Indication

Aspirin COX inhibitor Irreversible <60min 10 days 300mg then 75mg od 1 year

True allergy GI bleeding

All ACS

Clopidogrel Thienopyridine Irreversible 2-4 hrs 10 days/ 5 days

300-600 Then 75mg od 1 year

CURE

All ACS

Prasugrel Thienopyridine Irreversible 30min

10 days/ 7 days

60mg Then 10mg od 1 year

Previous CVA, >75years

TRITON TIMI -38

Stent thrombosis After angio and prior to PCI

Ticagrelor Cyclopentyl- triazolopyrimidine

Reversible 30min 3-4 days/ 5 days

180mg then 90mg BD 1 year

Bradycardia, dyspnoea

PLATO

All ACS

Cangrelor IV only

Stabilised ATP analogue

Reversible 2-3 min

1-2hrs /1 hr

Bolus 30ug/kg and infusion 4ug/kg/min

CHAMPION PHOENIX (VS ASPIRIN & CLOPID)

ALL ACS

Anti-platelet therapy in ACS NSTEACS • 1 year aspirin & clopidogrel (CURE) • Prolonged clopid (2.5yrs) vs 1 yr

associated with reduced recurrent MI but increased bleeding (DAPT)

• Prasugrel/aspirin superior to clopid/aspirin (TRITON TIMI 38)

• Ticagrelor/aspirin superior than clopid/asp (PLATO)

STEMI • Ticagrelor or Prasugrel 1 year superior

to clopidogrel • Prasugrel not for >75years

Heparins

• Unfractionated

- combined with aspirin given for 48hrs of benefit

c.f aspirin alone

• LMWT heparin (eg enoxaparin, daltaparin)

- as effective as unfractionated heparin (FRIC)

- superior to unfractionated heparin (ESSENCE,TIMIIIB)

- prolonged Rx (3/12) not superior to short term Rx (FRISC II)

- recommended length of Rx 2-8 days

• Factor Xa Fondaparinux in NSTEACS (OASIS5) and STEMI (OASIS6)

– Non-inferior to enoxaparin

– Given up to 8 days (mean 6 days)

– 50% reduction in bleeding compared to enoxaparin

Factor Xa Inhibitors and ACS (ATLAS ACS 2 TIMI 51)

• Concept that thrombin

generation persists > 6 months after MI

• Warfarin is associated with MI reduction by 44% in ACS meta-analyses

• Could prolonged Factor Xa inhibition with Rivaroxaban reduce recurrent thrombotic events?

• Randomised trial of 2.5mg BD vs 5mg BD vs placebo in addition to standard DAPT (aspirin & clopidogrel) for 2 years

Incidence of the Primary Efficacy Endpoint

The primary efficacy endpoint consists of cardiovascular death, myocardial infarction

(MI), or stroke. Data are presented for the rivaroxaban doses combined compared with

placebo. CI = confidence interval; HR = hazard ratio; ITT = intention-to-treat; mITT =

modified ITT.

What about warfarin: WOEST trial warf & clopid vs warf/asp/clopid n= 573 1:1 randomisation De Wilde Lancet 2013

0

5

10

15

20

25

30

35

40

45

50

TIMI

Minimal

TIMI Minor TIMI Major Any TIMI

bleeding

Doubletherapygroup

Tripletherapygroup

0

1

2

3

4

5

6

7

8

9

Death MI TVR Stroke ST

Doubletherapy group

Triple therapygroup

P < 0.001 except TIMI major p=ns

P ns for all

Antithrombotic strategies in patients with non-ST-elevation acute coronary

syndromes (NSTE-ACS) and non-valvular atrial fibrillation.

Marco Roffi et al. Eur Heart J 2016;37:267-315

ANTI-THROMBOTIC MEDICATION: KEY MESSAGES • Aspirin together with a novel P2Y12 inhibitor should

be given for 1 year after ACS

• Fondaparinux is the preferred LMWT in view of lower bleeding risk

• Prolonged treatment with low dose Rivaroxaban may play a role in reducing recurrent events in addition to clopidogrel/aspirin (not Ticagrelor)

• Clopidogrel and warfarin (without aspirin) can be used safely after coronary stenting in ACS

Can we identify the vulnerable patient?

PROSPECT trial Stone GW eta l NEJM 2011:364;226-235

• 700 patients with ACS

• 3 vessel coronary imaging (IVUS)

• 3 year follow up of recurrent events

• Lesion characteristics independently predicting events

– Thin cap fibroatheroma

– Plaque burden >70%

– Minimum luminal area <4mm2

PROSPECT: MACE M

AC

E (

%)

Time in Years

0 1 2 3

All

Culprit lesion (CL) related

Non culprit lesion (NCL) related

Indeterminate

0

5

10

15

20

25

Number at risk

20.4%

12.9%

11.6%

2.7%

13.2%

7.9%

6.4%

0.9%

18.1%

11.4%

9.4%

1.9%

ALL 697 557 506 480

CL related 697 590 543 518

NCL related 697 595 553 521

Indeterminate 697 634 604 583

Summary • Management of ACS has transformed over

recent years driven by: – Earlier diagnosis

– Better risk stratification

– Early angiography and revascularisation

– Improved anti-thrombotic medication

– Better outcomes

• Future horizons – Identifying vulnerable patients

– Optimising secondary prevention to stop recurrent events

THANK YOU