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!!