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 1.24 million Admissions per year STEMI 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
Risk Stratified by ECG findings Savonitto, S. et al. JAMA 1999;281:707-713. Copyright restrictions may apply.
Risk Stratification-Biomarkers Troponin hscrp, WBC, IL-6 Myeloperoxidase scd40 ligand Creatinine BNP Many others
Troponin and hs-crp and prognosis in ACS Both positive Either Positive % Mortality at 14 days Both Negative 0 2 4 6 8 10 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 % Death/MI/UR at 14 days 45 40 35 30 25 20 15 10 5 0 40.9 26.2 19.9 13.2 8.3 4.7 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 Tactics TIMI -18 NEJM 2001 25 24.5 % Death/MI/Ref ISchemia 20 15 10 5 0 16.4 16.6 15.1 TnI>0.1 TnI<0.1 Conserv Invasive
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? Major Bleeding by Aspirin Dose 5 4 3 2 1 0 75-100 mg 100-199 mg 200-325 mg ASA+PLVX ASA ASA ASA+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.
Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) A Algorithm for Patients with UA/NSTEMI Select Management Strategy Invasive Strategy Init ACT (Class I, LOE: A) Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B) Prior to Angiography Init at least one (Class I, LOE: A) or both (Class IIa, LOE: B) of the following: B B1 Proceed with an Initial Conservative Strategy Clopidogrel IV GP IIb/IIIa inhibitor B2 Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include: Delay to Angiography High Risk Features Early recurrent ischemic discomfort Proceed to Diagnostic Angiography Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.
Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy (Continued) Any subsequent events necessitating angiography? (Class I, LOE: A) Yes D No M EF 40% or less L Evaluate LVEF N EF greater than 40% (Class IIa, LOE: B) Stress Test O (Class I, LOE: B) (Class IIa, LOE: B) Proceed to Dx Angiography (Class I, LOE: A) E-1 E-2 Not Low Risk Low Risk (Class I, LOE: A) K 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) Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 8. ACT = anticoagulation therapy; LOE = level of evidence.
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 10 9 9.0 8 7 7.3 6 5.7 5.8 Enoxaparin 5 Fondaparinux 4 4.1 3 2 2.2 1 0 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 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 *p for noninferiority; p for superiority. Yusuf S, et al. N Engl J Med 2006;354:1464 76.
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 Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) Select Management Strategy Invasive Strategy Init ACT (Class I, LOE: A) Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B) B A B1 Proceed with an Initial Conservative Strategy 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 B2 Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include: Delay to Angiography High Risk Features Early recurrent ischemic discomfort Proceed to Diagnostic Angiography Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.
Acuity Trial -Heparin+IIb/IIa vs Bivalirudin in ACS 12 10 65% on plavix 8 6 4 Bivalirudin UFH+IIb/IIIa 2 0 Comp Ischemia 30 days Major Bleeding Net Clnical Outcome Stone GW et al; N Engl J Med 2006;355:2203-16.
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 Ticagrelor 90 mgor Prasugrel are options BID 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
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!!