Acute Coronary Syndromes January 9, 2013 Chris Chiles M.D. FACC

Disclosures  None- not even a breakfast burrito from a

drug company

Hospitalizations in the U.S. Due to ACS

Acute Coronary Syndromes*

1.57 Million Hospital Admissions - ACS

UA/NSTEMI† STEMI

1.24 million Admissions per year

0.33 million Admissions per year

*Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA. Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69–171.

Goals  Try not to get overwhelmed with the

clinical trial data  Better understand the two basic steps in

ACS management   Risk stratification   Therapy decisions

Pathophysiology of atherothrombosis  Plaque rupture

  Occurs as a result of thin cap with a soft lipid core.

  Macrophages and smooth muscle cells infiltrate the lesion. Cytokines, metaloproteinases, elastases, collagenases, all are elucidated.

 Dynamic platelet –fibrin thrombus.  Less likely vasoconstriction, progressive

mechanical obstruction

Acute Coronary Syndrome  Risk stratification

  Clinical features   Laboratory features

Clinical Presentation  Chest Pain with at least one of the following features

 At rest  Severe pain, new onset  Crescendo pattern

 May be jaw, arm, or back discomfort  May mimic indigestion  Dyspnea  Delerium in the elderly

Initial Diagnostic Orders  ECG-serial tracings  CBC, Chemistries, PT, PTT  Chest X ray if not done in the ED  Biomarkers Q6-8 hrs  Lipid profile, transminases

Risk Stratification   Important in determining medical and

interventional therapies  There are useful clinical markers and

scores  Biomarkers have been an active area of

investigation.

Risk Stratification Clinical High Risk Features  Prolonged duration of discomfort or

recurrent pain  Hypotension, tachycardia, hypoxia  Rales, S3 or S4. MR murmur  Edema, cool extremities, delerium, or

oliguria

Copyright restrictions may apply.

Savonitto, S. et al. JAMA 1999;281:707-713.

Risk Stratified by ECG findings

Risk Stratification-Biomarkers  Troponin  hsCRP, WBC, IL-6  Myeloperoxidase  sCD40 ligand  Creatinine  BNP  Many others

Troponin and hs-CRP and prognosis in ACS

0 2 4 6 8 10

BothNegative

EitherPositive

Bothpositive

% Mortality at 14 days

From Morrow DA; TIMI 11 , A Substudy :JACC 31;1998.

Risk of Mortality Stratified by Troponin

Ohman et al.; Gusto IIa, NEJM 1996.

BNP and prognosis in ACS

From A to Z trial. Morrow DA JAMA. 2005;294:2866-2871

WBC count, the poor man’s hsCRP

Mueller C et al.;Heart 2003;89:389–392

Risk Stratification- TIMI Risk score

4.78.3

13.2

19.9

26.2

40.9

051015202530354045

% D

eath

/MI/U

R a

t 14

days

0/1 2 3 4 5 >6

-Age > 65 >2 anginal episodes

 3 CAD RF -ST changes

 Known >50% stenosis +cardiac biomarkers

 Prior ASA

Risk Stratification- What you need to know.  You need to determine the patients risk

of adverse events.   TIMI Risk score   Multiple biomarkers ( practically troponin,

BNP, and WBC will be sufficient)

 Patients at high risk derive benefit from more aggressive strategies of both medical and invasive management.

Risk Stratification  Low Risk (14 day

death 0.4%)  Aspirin  Nitrates  Beta blocker  Statin  Outpatient stress test

 High Risk (14 day mortality 9.1 % )

 LMWH  “Other“

antithrombotics  +/- IIB /IIIA inhibitor  Clopidogrel/

Prasugrel/Ticagrelor   Invasive approach

urgently

Now that you risk stratified the patient, what do you do next?  Need to determine which therapies to

employ. As above, the impact of the therapy is dependent on how low/high risk the patient is.

Efficacy of IIb/IIIa inhibitors by Troponin Status

Invasive vs. Conservative Approach by TnI

24.5

16.4 16.615.1

0

5

10

15

20

25

% D

eath

/MI/R

ef IS

chem

ia

TnI>0.1 TnI<0.1

Tactics TIMI -18 NEJM 2001

ConservInvasive

Aspirin  Dose is important?

325 mg 1300 mg 650 mg 75 mg

Kaplan- Meyer Curve OASIS–7 trial NEJM 2010

Aspirin dose systematic review JAMA 2007

Aspirin dose-why is it important?

012345

75-100 mg

100-199mg

200-325mg

ASAASA+PLVX

Major Bleeding by Aspirin Dose

ASAASA+PLVX

From Cure trial Yusuf S NEJM 2000

Illustration Noncardiac CP

 History is important (did the patient just eat a turkey leg?) Unstable angina is a clinical diagnosis.

Algorithm for Patients with UA/NSTEMI

Proceed to Diagnostic Angiography

ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I,

LOE: A)

Diagnosis of UA/NSTEMI is Likely or Definite

Invasive Strategy Init ACT (Class I, LOE: A)

Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B)

Select Management Strategy Proceed with an

Initial Conservative

Strategy

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.

A

B

B1

B2

Prior to Angiography Init at least one (Class I, LOE: A) or

both (Class IIa, LOE: B) of the following:

Clopidogrel IV GP IIb/IIIa inhibitor

Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include:

Delay to Angiography High Risk Features

Early recurrent ischemic discomfort

Any subsequent events necessitating angiography?

EF greater than 40%

Evaluate LVEF

Low Risk

Cont ASA (Class I, LOE A) Cont clopidogrel (Class I, LOE A) and ideally up to 1 yr (Class I, LOE B)

DC IV GP IIb/IIIa if started previously (Class I, LOE A) DC ACT (Class I, LOE A)

(Class I, LOE: B)

Proceed to Dx Angiography

Yes

EF 40% or less Stress Test

(Class I, LOE: A)

No

Not Low Risk

(Class IIa, LOE: B)

Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy

(Continued)

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 8. ACT = anticoagulation therapy; LOE = level of evidence.

(Class I, LOE: A)

(Class IIa, LOE: B)

O

L

MN

K

E-1 E-2

D (Class I, LOE: A)

Summary of Low Risk  Aspirin  Fondaparinux, Heparin, or LMWH  Clopidogrel

  Ticagrelor  Nitrates as needed  Beta blockers, ACE inhibitors  Check Lipids

  Treat aggressively-LDL <70 mg/dl  Stress testing inpt or as outpatient in 72 hrs.  Risk factor modification-smoking, DM, HTN

Anticoagulant therapy in ACS  There are a ton of choices and

combinations are currently mind boggling.

  I calculate at least 96 possible combinations of antiplatelet/antithrombotic medical therapies.

  Let’s distill it to something reasonable…

UF Heparin vs. LMWH

LMWH  Don’t use if significant renal dysfunction

(Cr. Cl. <30 ml/min)  1 mg/kg SQ Q12h  ? Less likely if patient going to cath/

depends on where you practice

OASIS 5 Cumulative Risk of Death, MI, or Refractory Ischemia

*p for noninferiority; †p for superiority. Yusuf S, et al. N Engl J Med 2006;354:1464–76.

5.7

4.1

9.0

5.8

2.2

7.3

0 1 2 3 4 5 6 7 8

9 10

OASIS 5 Death, MI, or refractory ischemia at 9 days OASIS 5 Major bleeding at 9

days OASIS 5 Composite primary outcome and major bleeding at 9 days

Enoxaparin

Fondaparinux

Absolute Risk Reduction -0.1 1.9 1.7 Hazard Ratio 1.01 0.52 0.81 Confidence Interval 0.90–1.13 0.44–0.61 0.73–0.89 p 0.007* < 0.001† < 0.001†

Oasis-5 trial

Yusuf S, et al. N Engl J Med 2006;354:1464–76.

Fondaparinux  2.5 mg SQ daily  Don’t use if significant renal dysfunction

(Cr. Cl. <30 ml/min)  Use if medical management is planned   Increased risk of catheter thrombosis in

OASIS -5

My suggestion for probable low risk patients  ASA 162-325mg, then 81 mg daily.  Clopidogrel load 300 mg, then 75 mg

daily  Fondaparinux if clearly medical

management   UFH if pt. with renal failure and/or patient

risk is unclear   Lovenox could be used, but not if patient

has higher bleeding risk or renal failure

Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy

Proceed to Diagnostic Angiography

ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I,

LOE: A)

Diagnosis of UA/NSTEMI is Likely or Definite

Invasive Strategy Init ACT (Class I, LOE: A)

Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B)

Select Management Strategy Proceed with an

Initial Conservative

Strategy

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.

A

B

B1

B2

Prior to Angiography Init at least one (Class I, LOE: A) or

both (Class IIa, LOE: B) of the following:

Clopidogrel IV GP IIb/IIIa inhibitor

Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include:

Delay to Angiography High Risk Features

Early recurrent ischemic discomfort

Acuity Trial -Heparin+IIb/IIa vs Bivalirudin in ACS

0

2

4

6

8

10

12

CompIschemia30 days

MajorBleeding

NetClnicalOutcome

Bivalirudin

UFH+IIb/IIIa

Stone GW et al; N Engl J Med 2006;355:2203-16.

65% on plavix

When to use a gp IIb/IIIa inhibitor  Not routinely  Patients who are high risk ( Troponin

positive) with recurrent or ongoing pain.  Acceptable to give in the cath lab at

time of PCI  Not in those with advanced CKD or high

bleeding risk

When to use a gp IIb/IIIa inhibitor  EARLY ACS trial. NEJM May 21, 2009

  No difference in 30d death/mi/thrombosis between routine early use of eptifibatide and provisional use at the time of PCI.

  Increase in bleeding and need for transfusion 1.5-2.0 fold in the routine early use

 Acuity timing trial. JAMA Feb 14,2007   Routine upstream use was of unclear benefit, possible

benefit of early use but not statistically significant.   Increased bleeding in early use by 1.2 % absolute.

Ticagrelor  Direct , rapidly acting inhibitor of the

platelet  The PLATO trial showed a significant

reduction in mortality using ticagrelor as compared to clopidogrel   Slight increase in ICH although overall major

bleeding was equivalent   NEJM Sept. 9, 2010

My suggested approach to anticoagulation in high risk patients going to cath.

 Plavix 600 mg   or Prasugrel are options

 Bivalirudin 0.1mg/kg bolus, then 0.25 mg/kg/hr infusion (only if you have given plavix or ticagrelor.)  Lovenox 1 mg/kg SQ Q12h if you are waiting

a few days instead of bival ??  UFH if Cr Cl <30 ml/min

 Occasional use of IIb/IIIa inhibitor  Try not to switch strategies in the middle

Ticagrelor 90 mg BID

Summary-my approach  First, stratify risk to determine treatment

approach  All patients get ASA 81 mg, Plavix or

Ticagrelor, statin, beta blocker, SL NTG  Some get nitrates, ACE inhibitor/ARB  Low risk get fondaparinux and a stress test  High risk get bivalirudin and a cath

May your next ACS patient have classic symptoms and clear choices for management. THANKS!!