Download Management of Acute Coronary Syndromes

Management of Acute Coronary Syndromes
Julio A. Panza, MD, FACC, FAHA
Division of Cardiology, Washington Hospital Center
Professor of Medicine, Georgetown University
Washington Metropolitan Society of Health-System Pharmacists
2013 Annual Meeting
There are no conflicts of interest related to this presentation
Learning Objectives
• Explain the variability in the clinical presentation of ACS
• Recognize the currently available tools for diagnosis and risk
stratification
• Discuss the clinical management of ACS based on the
presentation type, severity of disease, comorbid disease, and
other preexisting conditions
• Reinforce key educational concepts and what the guidelines
and recommendations are for the spectrum of ACS
Goals of ACS Management
STEMI:
• Immediate reperfusion
All ACS:
• Stabilize and “passivate” the acute coronary lesion
– Prevent further thrombosis
– Allow endogenous dissolution of the thrombus
– Reduce stenosis
• Relieve ischemia
• Prevent serious adverse outcomes (i.e., death or MI)
• Provide long-term secondary prevention
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Cannon CP, Braunwald E. Unstable angina and non-ST elevation myocardial infarction. In: Bonow RO,
Mann DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1178-1209.
In-hospital Care: Treatment Settings
Setting
Patients
Capabilities
Cardiac Catheterization
Laboratory (Cath Lab)
Invasive
therapy/
reperfusion
Angiography
High-risk
patients
Continuous rhythm monitoring
Coronary care unit (CCU) or
Intensive care unit (ICU)
PCI
Invasive procedures
Frequent vital sign and mental
status assessment
Rapid defibrillation capability
Specialist staff
Step-down or
general medical unit
Low-risk
patients
Continuous rhythm monitoring
Observation for recurrent ischemia
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Summary of Treatment Strategies for
ACS
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
ED assessment and general treatment
ECG
Normal or nondiagnostic
ST elevation
STEMI
Early hospital
care
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
Lower-risk UA/NSTEMI
High risk
Low risk
Continued observation
and testing
ECG
Troponins
Stress test
No evidence of ACS
Discharge with follow-up
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Summary of Treatment Strategies for ACS:
Prehospital Management
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
ED assessment and general treatment
ECG
Normal or nondiagnostic
ST elevation
STEMI
Early hospital
care
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
Lower-risk UA/NSTEMI
High risk
Low risk
Continued observation
and testing
ECG
Troponins
Stress test
No evidence of ACS
Symptoms suggestive of ACS
EMS transport and care
Discharge with follow-up
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Summary of Treatment Strategies for
ACS: ED Management
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
ED assessment and general treatment
ECG
Normal or nondiagnostic
ST elevation
STEMI
Early hospital
care
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
Lower-risk UA/NSTEMI
High risk
Continued observation
and testing
ECG
Troponins
Stress test
ED assessment and general treatment
Low risk
No evidence of ACS
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
Discharge with follow-up
ECG
ST elevation
Suspicious
STEMI
High-risk
UA/NSTEMI
Normal or
nondiagnostic
Lower-risk
UA/NSTEMI
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Summary of Treatment Strategies for
ACS: Early Hospital Management
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
STEMI
ECG
STEMI
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
Lower-risk
UA/NSTEMI
Normal or nondiagnostic
ST elevation
Early hospital
care
High-risk
UA/NSTEMI
ED assessment and general treatment
Adjunctive medical
therapy
Reperfusion
(fibrinolytics or PCI)
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
Lower-risk UA/NSTEMI
High risk
Low risk
Continued observation
and testing
ECG
Troponins
Stress test
Consider early
invasive strategy
No evidence of ACS
High
risk
Discharge with follow-up
Adjunctive medical
therapy
Low
risk
Continued
observation and
testing
ECG
Troponins
Stress test
No evidence
of ACS
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Summary of Treatment Strategies for
ACS: Medical Management
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
ED assessment and general treatment
ECG
Normal or nondiagnostic
ST elevation
STEMI
Early hospital
care
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
Lower-risk UA/NSTEMI
Agents Used in Adjunctive Medical Therapy/ Medical
Management
High risk
Low risk
Continued observation
and testing
ECG
Troponins
Stress test
Antiplatelet agents and
anticoagulants
No evidence of ACS
Discharge with follow-up
Other agents
• Nitroglycerin
• Heparin (UFH and LMWH)
• Analgesics
• Direct thrombin inhibitors
• RAAS inhibitors
(ACE inhibitors,
ARBs)
• Aspirin
• Thienopyridines
• Gp IIb/IIIa inhibitors
• Warfarin
• Glucose control
• Risk factor
management
• Magnesium
• CCBs
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Summary of Treatment Strategies for
ACS: Reperfusion
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
ECG
STEMI
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
 Restoration of blood flow to the infarct area
Normal or nondiagnostic
ST elevation
Early hospital
care
Reperfusion
ED assessment and general treatment
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
 STEMI: faster reperfusion = better outcomes
Lower-risk UA/NSTEMI
High risk
Continued observation
and testing
ECG
Troponins
Stress test
Percutaneous coronary intervention (PCI)
 Also known as percutaneous transluminal coronary
angioplasty (PTCA)
Low risk
No evidence of ACS
 Invasive technique: a catheter is used to
mechanically open the occluded artery
Discharge with follow-up
 Preferred if available promptly
Fibrinolysis
 IV agents that dissolve thrombi by attacking fibrin
 Increases bleeding risk
 Used when prompt PCI is not available
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Summary of Treatment Strategies for
ACS: Late Hospital Care
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
ED assessment and general treatment
ECG
Normal or nondiagnostic
ST elevation
STEMI
Early hospital
care
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
Lower-risk UA/NSTEMI
High risk
Low risk
Continued observation
and testing
ECG
Troponins
Stress test
No evidence of ACS
Discharge with follow-up
Continue medical therapy
and monitoring
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Summary of Treatment Strategies for
ACS: Postdischarge Care
Prehospital
Symptoms suggestive of ACS
EMS transport and care
ED
ED assessment and general treatment
ECG
Normal or nondiagnostic
ST elevation
STEMI
Early hospital
care
Suspicious
High-risk UA/NSTEMI
Adjunctive medical therapy
Reperfusion
(fibrinolytics or PCI)
Consider early invasive
strategy
Adjunctive medical therapy
Late hospital
care
Postdischarge
Secondary
prevention
Continue medical therapy and monitoring
Discharge with follow-up
Secondary prevention
Lower-risk UA/NSTEMI
High risk
Low risk
Continued observation
and testing
ECG
Troponins
Stress test
No evidence of ACS
Discharge with follow-up
Discharge with follow-up
Secondary prevention
Adapted from O'Connor RE, Brady W, Brooks SC, et al. Circulation. 2010;122:S787-S817.
Reperfusion and Revascularization
Reperfusion: restoration of blood supply to a tissue
or organ to relieve ischemia
• Fibrinolysis
• PCI (also known as angioplasty or PTCA)
Revascularization: restoration of flow through part
of the vascular system
• PCI
• CABG (coronary artery bypass grafting)
Importance of Rapid Reperfusion in STEMI
“…Expeditious restoration of flow in the
obstructed infarct artery after the onset of
symptoms in patients with STEMI is a key
determinant of short- and long-term
outcomes…”
30 minutes of delay = 8% increase in relative risk
of 1-year mortality
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Antman E, Morrow DA. ST-segment elevation myocardial infarction: management. In: Bonow RO, Mann
DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1111-1177.
Coronary Angiography and PCI
Angiography
• Thread a balloon-tipped catheter to the occluded coronary
artery using x-ray guidance
• Inject a contrast medium to make the artery visible by x-ray
PCI
• Inflate the balloon to open the lumen (balloon angioplasty)
• Usually, deploy a stent to prevent vessel closure
American Heart Association. Cardiac procedures and surgeries.
http://www.heart.org/HEARTORG/Conditions/HeartAttack/PreventionTreatmentofHeartAttack/CardiacProcedures-and-Surgeries_UCM_303939_Article.jsp. Updated May 2, 2011. Accessed May 5, 2011.
Popma JU. Coronary arteriography. In: Bonow RO, Mann DL, Zipes P, et al, eds. Braunwald's Heart
Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2011:406-440.
PCI: Stents
• Metal mesh tubes used to hold
the artery open (prevent acute vessel closure)
• Stent types:
– Bare-metal stent (BMS)
– Drug-eluting stent (DES)
Complications of Stents
In-stent Restenosis:
• Recurrent narrowing within the stent
• Results from excessive smooth muscle cell (SMC) proliferation within
the stent
Stent thrombosis:
• Thrombus develops in the stent
• Causes include exposure of blood and plaque to the stent material and
inflammation caused by the stent
• Risk is reduced as the neointima (new intimal layer) heals and covers
the stent material
Bare-metal Stents (BMS)
• Uncoated metal mesh
• Prevents acute vessel closure
• Effects on restenosis
– Short term: reduces restenosis by increasing lumen opening at the
procedure
– Long term: induces SMC proliferation, leading to increased restenosis
• Used in 10%–30% of patients undergoing PCI
• Restenosis rates
– Angiographic restenosis: 20%–30% of patients
– Clinical restenosis: 10%–15% of patients
Popma JU. Coronary arteriography. In: Bonow RO, Mann DL, Zipes P, et al, eds. Braunwald's Heart
Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2011:406-440.
Drug-eluting Stents (DES)
• Metal mesh coated with a material that
reduces the risk of restenosis by releasing
(eluting) a medication that slows SMC proliferation
• Several types coated with different agents are available
• Comparison to BMS:
– Advantage: reduced restenosis rates
– Disadvantage: requires a longer duration of dual antiplatelet therapy
(aspirin + thienopyridine) to prevent stent thrombosis; increases
bleeding risk
– BMS favored for low bleeding risk
Popma JU. Coronary arteriography. In: Bonow RO, Mann DL, Zipes P, et al, eds. Braunwald's Heart
Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2011:406-440.
Kushner FG, Hand M, Smith SC, et al. Circulation. 2009;120:2271-2306.
Technical Issues in PCI
• Access route
– Femoral (groin) vs Radial (wrist)
– Brachial (armpit) and antecubital (elbow) are
rarely used
• Restenosis
– POBA (plain old balloon angioplasty) vs
PCI (stent placement)
• Vascular access and closure devices
Fibrinolysis
Description
•
•
Promotes clot dissolution by activating the fibrinolytic (fibrin-dissolving) system
Also known as fibrinolytic therapy, thrombolysis, or thrombolytic therapy
Agents
•
Streptokinase, alteplase, reteplase, tenecteplase-tPA
Benefits
•
•
Clear mortality reduction when used early in STEMI
Not beneficial in NSTEMI
Adverse effects
•
Increased bleeding risk (e.g. intracranial hemorrhage)
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292. Zehnder JL. Drugs used in
disorders of coagulation. In: Katzung BG, ed. Basic and Clinical Pharmacology. 10th ed. New York, NY:
McGraw Hill; 2007:542-559.
Selection of Reperfusion Therapy in STEMI
First choice: PCI
• Within 90 minutes (first contact-to-balloon time)
• If PCI is indicated or fibrinolysis is contraindicated
Second choice: Fibrinolysis within 30 minutes if
PCI is not available within 90 minutes
Rescue PCI: Performed if fibrinolysis fails to
restore flow
Antman EM, Hand M, Armstrong PW, et al. Circulation. 2008;117:296-329.
Indications for PCI
• Cardiogenic shock
• Killip class ≥3
• Late presentation (>3 hours)
• Diagnosis in doubt
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Contraindications for Fibrinolysis
Absolute contraindications
Relative contraindications
•
Any prior intracranial hemorrhage
•
•
Known cerebral lesions (structural or cancer)
•
Ischemic stroke within 3 months (unless
within 3 hours)
•
•
Suspected aortic dissection
•
Active bleeding (excluding menses)
•
Significant closed-head or facial trauma within
3 months
•
•
•
•
•
•
•
•
History of chronic, severe, poorly controlled
hypertension
Severe uncontrolled hypertension on presentation
(SBP >180 mm Hg or DBP >110 mm Hg)
History of prior ischemic stroke, dementia, or known
intracranial pathology not covered in
contraindications
Recent (<3 weeks) traumatic or prolonged (>10
minutes) CPR or major surgery
Recent internal bleeding (within 2–4 weeks)
Noncompressible vascular punctures
Prior exposure (>5 days ago) or prior allergic
reaction to certain fibrinolytic agents
Pregnancy
Active peptic ulcer
Current use of anticoagulants
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Other Techniques: Facilitated PCI
• Planned use of fibrinolysis with PCI
• Not used in UA/NSTEMI
• Proven harmful with full-dose fibrinolytics; not
recommended
• May be considered with less than full-dose fibrinolytics
• PCI is generally preferred if it can be performed in a
timely manner
Antman EM, Hand M, Armstrong PW, et al. Circulation. 2008;117:296-329.
Other Techniques: Thrombectomy
• Intravascular thrombus fragments may cause distal embolism
– Possible obstruction of microvascular beds
– Possible impairment of tissue level reperfusion (no-reflow condition)
• Thrombectomy: variety of techniques used to remove the
intravascular thrombus
• Thrombus aspiration: thrombus is suctioned into a catheter
• Embolic protection: devices to trap thrombus fragments
• Manual thrombus aspiration improves mortality in primary PCI
Bavry AA, Kumbhani DJ, Bhatt DL. Eur Heart J. 2008;29:2989-3001.
Popma JU. Coronary arteriography. In: Bonow RO, Mann DL, Zipes P, et al, eds. Braunwald's Heart
Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2011:406-440.
Kushner FG, Hand M, Smith SC, et al. Circulation. 2009;120:2271-2306.
Other Techniques: CABG (Coronary Artery
Bypass Grafting)
• Surgery to improve perfusion by repairing or circumventing
the atherosclerotic artery or arteries with blood vessels taken
from elsewhere in the body
• STEMI: largely superseded for acute reperfusion by fibrinolysis
and PCI; still used for some patients
• UA/NSTEMI: recommended for severe CAD (e.g., >50%
stenosis of the left main artery or 3-vessel disease) and when
PCI is not feasible
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292. Morrow DA, Boden WE. Stable
ischemic heart disease. In: Bonow RO, Mann DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed.
Philadelphia, PA: Elsevier Saunders; 2011:1210-1269.
TIMI Flow Grading System
TIMI: Thrombosis in Myocardial Infarction Study Group
Used in coronary angiography to describe flow and restoration of
flow
Grade
0
1
2
3
Description
Complete occlusion of the infarct-related artery
Some penetration of the contrast material beyond the point of
obstruction but without perfusion of the distal coronary bed
Perfusion of the entire infarct vessel into the distal bed but with
delayed flow compared with a normal artery
Full perfusion of the infarct vessel with normal flow
Goal: TIMI 3
Antman E, Morrow DA. ST-segment elevation myocardial infarction: management. In: Bonow RO, Mann
DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1111-1177.
TIMI Flow
Images published in Braunwald's Heart Disease. 9th ed. Philadelphia, PA, Antman E, Morrow DA.© Elsevier.
Impact of TIMI Flow
TIMI 1
TIMI 2
TIMI 3
Images published in Braunwald's Heart Disease. 9th ed. Philadelphia, PA, Antman E, Morrow DA.© Elsevier.
Myocardial Blush
• Angiographic measure of blood flow through
the microvasculature in the territory at risk
• TIMI myocardial perfusion grading system
extends TIMI flow grades
– Usually when TIMI 3 flow is achieved
– Measures dye in blood
TIMI Myocardial Perfusion Grade
TMP Grade
Description
3
2
1
0
Normal entry and Delayed entry and Dye enters slowly Dye does not
but does not exit enter the microexit of dye
exit of dye
vasculature
Image
Reproduced from Heart, Appleby M A, Angeja BG, Dauterman K.;85(5):485-86.2001.with permission from BMJ Publishing Group Ltd.
Reproduced from Heart, Appleby M A, Angeja BG, Dauterman K., Gibson C, 85 (5); 485-86, 2001 with
permission from BMJ Publishing Group Ltd.
Myocardial Blush and Mortality
Reproduced from Heart, Appleby M A, Angeja BG, Dauterman K.;85(5):485-86.2001.with permission from BMJ Publishing Group Ltd.
Reproduced from Heart, Appleby M A, Angeja BG, Dauterman K., Gibson C, 85 (5); 485-86, 2001 with
permission from BMJ Publishing Group Ltd.
Medical Therapy
Therapy
Clinical Role
Antiplatelet therapy
Establishes and maintains patency of the occluded artery
Reduces the risk of recurrent thrombosis
Anticoagulant therapy
Must balance benefits against increased bleeding risk
Antiischemic therapy
Prevents or minimizes ischemic symptoms
RAAS inhibitors (ACE
inhibitors, ARBs)
Control blood pressure
Analgesics
Pain relief
Anxiolytics
Anxiety management
Minimize ventricular remodeling and other
consequences
Antiplatelet Therapy
Usually includes long-term dual antiplatelet therapy (DAPT or DAT;
aspirin + a thienopyridine)
Agent
Route
Aspirin
Oral
Lifelong use recommended for all patients
without contraindications
Thienopyridines
Oral
Long-term use in DAPT
Gp IIb/IIIa inhibitors
IV
Clinical Role and Key Concerns
Reasonable at the time of PCI
May be used for unstable or high-risk patients at
presentation
Bleeding is the most important adverse effect and may be life threatening (e.g., peptic
ulcer, intracerebral hemorrhage)
Aspirin
Give as early as possible, continue indefinitely
• Regardless of reperfusion strategy
• Regardless of other antiplatelet agents
• Contraindications: Aspirin allergy
Dosage
• Initial dose: 162 mg–325 mg
• Maintenance dose: indefinite oral daily dose of 75 mg–162
mg
• If used with ticagrelor, dose <100 mg/day
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Thienopyridines: Overview
Agent
Included in Guideline Recommendations
Clopidogrel
Yes
Prasugrel
Yes
Ticagrelor
No, due to recent release (July 2011)
Ticlopidine
Not recommended due to adverse effects
Effient (prasugrel) [package insert]. Indianapolis, IN: Daiichi Sankyo, Inc. and Eli Lilly and Company; 2010.
Plavix (clopidogrel) [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals
Partnership; 2010.
Thienopyridines: Use in ACS
Timing
• Start early
• Loading dose before angiography/PCI
• Continue for 1–12 months (no reperfusion, fibrinolytics, or
BMS), or >12 months (DES)
Choice of agent
• Consider a more potent agent (prasugrel or ticagrelor) if
thrombosis risk outweighs bleeding risk
Kushner FG, Hand M, Smith SC, et al. Circulation. 2009;120:2271-2306.
Wright RS, Anderson JL, Adams CD, et al. J Am Coll Cardiol. 2011.
Antman EM, Hand M, Armstrong PW, et al. Circulation. 2008;117:296-329.
CURE
Trial design: clopidogrel 300 mg loading dose followed by 3-12 months maintenance therapy vs
placebo
(P<0.001)
% of Patients
Results
• Primary endpoint (CV death, MI, or stroke): 9.3%
clopidogrel vs 11.4% placebo, P<0.001
11.4
12
10
(P=0.001)
• 2nd Primary endpoint (primary endpoint + refractory
ischemia): 16.5% clopidogrel vs 18.8% placebo,
P<0.001
9.3
8
• Major bleeding: 3.7% clopidogrel vs. 2.7% placebo,
P=0.001
6
3.7
4
2.7
2
• Life-threatening bleeding: 2.2% clopidogrel vs. 1.8%
placebo, P=0.13
Conclusions
0
Death, MI, or Stroke
Clopidogrel
(n = 6259)
Major bleeding
Placebo
(n = 6303)
• Clopidogrel loading dose + long-term therapy
reduce the rate of CV death, MI, stroke, and
refractory ischemia
• Bleeding risk increased
• Foundational study for the current use of
thienopyridines
CURE Investigators. N Engl J Med. 2001;345:494-502.
PCI-CURE
Trial design: substudy of CURE involving patients who underwent PCI, patients received
clopidogrel 300 mg loading dose followed by 3-12 months maintenance therapy vs
thienopyridine for 2-4 weeks after PCI
CV Death or MI
Results
• CV death or MI: 8.8% Clopidogrel vs. 12.6%
placebo, P=0.002
(P=0.002)
14
12.6
• No significant difference in major or lifethreatening bleeding
% of Patients
12
10
8.8
2
Conclusions
• Clopidogrel loading dose + long-term therapy
reduce the rate of CV death or MI by about
1/3 with no significant change in bleeding
rates
0
- Improves both early and late events
8
6
4
Clopidogrel
(n = 1313)
Placebo
(n = 1345)
• Foundational study for the current use of
thienopyridines
Mehta SR, Yusuf S, Peters RJ, et al. Lancet. 2001;358:527-533.
Glycoprotein IIb/IIIa Inhibitors:
Overview
Available agents
• Eptifibatide, tirofiban, abciximab
Use in ACS
• To reduce thrombosis risk in selected patients, e.g., those with
– High risk
– Insufficient thienopyridine preloading
– Large thrombus
• In combination with reduced-dose fibrinolytics for reperfusion
Timing
• Short-term: during the hospital stay
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Kushner FG, Hand M, Smith SC, et al. Circulation. 2009;120:2271-2306.
Wright RS, Anderson JL, Adams CD, et al. J Am Coll Cardiol. 2011.
Hanna EB, Rao SV, Manoukian SV, Saucedo JF. JACC Cardiovasc Interv. 2010;3:1209-1219.
ADMIRAL
Trial design: Patients with STEMI undergoing PCI were randomized to abciximab or placebo: bolus
before PCI and infusion for 12 hours after
Death, MI, or
Revascularization
(P=0.02)
18
TIMI Flow at 6
Months
120
15.9
16
100
12
10
7.4
6
4
% of Patients
% of Patients
14
8
(P=0.04)
2.9
TIMI 2
• Primary endpoint (Death, MI, or urgent target vessel
revascularization): 7.4% with abciximab vs 15.9% with
placebo, P=0.02
• Improved with abciximab:
80
–Procedural success (TIMI 3 and <50% stenosis)
(95.1% vs. 84.3%, P=0.01)
60
–6-month TIMI 3 or TIMI 2 flow (97.1% vs. 97.90%,
P=0.04)
94.3 TIMI 3
40
20
2
5.2
Results
82.8
–6-month LVEF (61.1±10.6% vs 57.0±11.1%,
P=0.05)
• No significant difference in major bleeding
0
0
Abciximab
(n = 149)
Conclusions
Placebo
(n = 151)
• Use of a Gp IIb/IIIa inhibitor at presentation
facilitates reperfusion and improves outcome
Montalescot G, Barragan P, Wittenberg O, et al. N Engl J Med. 2001;344:1895-1903.
ESPRIT
Trial design: Eptifibatide or placebo, double bolus followed by 18-24 hours continuous infusion,
with PCI after the 1st bolus, with aspirin, a thienopyridine, and possibly heparin
Death, MI, or urgent
revascularization,
thrombotic bailout
HR 0.63
P=0.0015
Major Bleeding
P=0.027
Results
• Composite primary endpoint of death, MI, urgent
target vessel revascularization, or thrombotic
bailout: eptifibatide 6.6%, placebo 10.5%,
P=0.0015
%
- Consistent across different components of
the endpoint
• Major bleeding: eptifibatide 1.0%, placebo 0.4%,
P=0.027
Conclusions
• A double bolus of eptifibatide is safe and
effective in reducing acute and 30 days adverse
outcomes in patients undergoing stent
implantation
Eptifibatide
(n=1040)
Placebo
(n=1024)
ESPRIT Investigators. Lancet. 2000;356:2037-2044.
Anticoagulant Therapy
Agent
In-hospital Anticoagulants
Route
Clinical Role and Key Concerns
Usually used only short term (48 hours to duration of
stay)
Heparin (UFH, LMWH)
IV
Historically the standard anticoagulant
Direct thrombin inhibitors
IV
May be used instead of heparin
Long-term Anticoagulants
If indications for anticoagulation are present
Warfarin
Oral
Difficult to manage dosage
Factor Xa inhibitors
Oral
Emerging as a possible alternative to warfarin
Bleeding is the most important adverse effect and may be life threatening (e.g., peptic
ulcer, intracerebral hemorrhage)
In-hospital Anticoagulant Therapy
Use in ACS
• Anticoagulant therapy should be added to antiplatelet
therapy as soon as possible after presentation
Timing
• Usually 48–72 hours, occasionally longer
Agents
• Unfractionated heparin (UFH)
• Low-molecular-weight heparin (LMWH) (enoxaparin,
fondaparinux)
• Direct thrombin inhibitors (bivalirudin)
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Choice of Anticoagulant
• Regimens with established efficacy
– Enoxaparin and UFH
– Bivalirudin and fondaparinux
– Conservative strategy: enoxaparin or UFH
• LMWH is easier to use than UFH in patients <75 years of age with
good renal function
• Bivalirudin is an alternative to UFH or LMWH
– Recommended for heparin-induced thrombocytopenia
• Fondaparinux is preferred in patients who have an increased risk of
bleeding
– Should not be the sole anticoagulant for PCI
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Kushner FG, Hand M, Smith SC, et al. Circulation. 2009;120:2271-2306.
Wright RS, Anderson JL, Adams CD, et al. J Am Col Cardiol. 2011.
ACUITY
Trial design: bivalirudin vs. bivalirudin + Gp IIb/IIIa inhibitor vs. heparin (UFH or enoxaparin) + Gp
IIb/IIIa inhibitor
P Values*
0.16
0.45
0.32 <0.0001
0.10 0.057
16
13
12
% of Patients
12
10
8
• Shown in chart
15
14
9
9
8
8
7
6
4
4
2
0
Ischemic events†
Heparins +
Gp IIb/IIIa
(n=2561)
Major Bleeding Net clinical outcome‡
Bivalirudin +
Gp IIb/IIIa
(n=2609)
Results
Bivalirudin
(n=2619)
Conclusions
• For patients undergoing PCI for
moderate- to high-risk NSTE ACS,
bivalirudin alone vs. comparators
provides:
- Similar net clinical outcomes
- Similar ischemic events
- Significantly lower bleeding
complications
- Upstream aspirin, clopidogrel, and
bivalirudin, with Gp IIb/IIIa inhibitors
only for refractory complications)
provide the best likelihood of eventfree survival in moderate and high-risk
ACS treated by PCI
*: P values vs heparin + Gp IIb/Iia inhibitor.
†: Ischemic events: composite of death, MI, unplanned revascularization for ischemia, and stent
thrombosis
‡: ischemic event or major bleeding
Stone GW, White HD, Ohman EM, et al. Lancet. 2007;369:907-919.
HORIZONS-AMI
Trial design: Patients presenting within 12 hours with a STEMI were randomized in a 1:1 fashion
to receive either bivalirudin alone or heparin plus Gp IIb/IIIa inhibitors. Clinical outcomes were
compared at 30 days.
Results
20
20
• Bivalirudin superior to hep+Gp Iib/IIIa for:
15
− 30-day adverse clinical events (9.2% vs. 12.1%;
P=0.005)
% of Patients
(P=0.005)
15
10
12.1
9.2
(P<0.001)
%
8.3
10
5
0
0
MACE + Major Bleeding
Bivalirudin
(n = 2,257)
− All-cause mortality (2.1% vs. 3.1%; P=0.047)
− Mortality advantage sustained for 1 year in highrisk patients
4.9
5
− Cardiac mortality (1.8% vs. 2.9%; P=0.03)
Major Bleeding
• Due to decreased major bleeding (4.9% vs.
8.3%; P<0.001)
Conclusions
Heparin + Gp IIb/IIIa
• Bivalirudin superior to heparin+ Gp IIb/IIIa for
(n = 749)
30-day adverse events and major bleeding
Parodi G, Antoniucci D, Nikolsky E, et al. JACC Cardiovasc Interv. 2010;3:796-802.
Long-term Anticoagulant Therapy
Use in ACS
• Not appropriate for all patients with ACS
• Used when indications for anticoagulation are present
– Atrial fibrillation
– Left ventricular thrombus
Coumadin (warfarin) [package insert]. Princeton, NJ: Bristol Meyers Squibb; 2010.
Agents for Long-term Anticoagulation
Warfarin
• Dosage chosen to achieve an INR 2.0–3.0
• Duration of therapy determined by clinical circumstances
• Difficult to manage due to narrow therapeutic window
– Requires close monitoring and frequent dose adjustment
Factor Xa inhibitors
• May be easier to manage than warfarin
• Not currently available for ACS
• In development: dabigatran, rivaroxaban, apixaban,
edoxaban, betrixaban
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Antman EM, Hand M, Armstrong PW, et al. Circulation. 2008;117:296-329.
Zikria J, Ansell J. Discov Med. 2009.
Anti-ischemic Therapy
Agent
Clinical Role and Key Concerns
Nitroglycerin
Vasodilation to reduce ischemia
Contraindicated with sildenafil (Viagra) or similar agents
Other nitrates
Isosorbide is used in treating stable angina; not
recommended for ACS
Beta-blockers
Control heart rate and contractility to minimize myocardial
oxygen demand and reduce ischemia
Use caution with IV beta-blockers in STEMI
Calcium channel blocker (preferably non-dihydropyridine) if
beta-blockers are contraindicated or not tolerated
Nitroglycerin
Use in ACS
• Cause vasodilation, reducing preload and afterload
• May relieve ischemia and ischemic pain
Available forms
• Sublingual, nasal spray, nitropaste, IV
Contraindications
• Hypotension
• Severe bradycardia (<50 bpm) or tachycardia (>100 bpm)
• Right ventricular infarction
• Sildenafil within 24 hours or tadalafil within 48 hours
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Hand M, Armstrong PW, et al. Circulation. 2008;117:296-329.
Beta-Blockers
Effects
• Reduce myocardial oxygen demand by reducing heart rate, contractility,
and blood pressure
• Cardioprotection
Use in ACS
• Start oral beta-blockers early and continue indefinitely for all patients
without contraindications
Contraindications
• Acute heart failure, low output state, or risk for cardiogenic shock
• Bradycardia
• Significant conduction abnormalities
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Hand M, Armstrong PW, et al. Circulation. 2008;117:296-329.
RAAS Inhibitors
Type of Agent
Clinical Role and Key Concerns
•ACEAngiotensin-converting
enzyme
(ACE)
•
All
patients,
especially
if
:
Inhibitor
40%
(Angiotensin
inhibitors -- LVEF
Hypertension, diabetes, chronic kidney disease
Converting Enzyme
- Intermediate or high risk
Inhibitor)
• Angiotensin• receptor
blockers (ARBs)
Start early and continue indefinitely
• Aldosterone
ARB
(Angiotensin
• inhibitors
Same as ACE inhibitors
Receptor Blocker)
• Use if ACE inhibitors are contraindicated or not
• Direct renin inhibitors
(not generally used in
tolerated
the setting
ACS)
• Add
to ACE inhibitor or ARB if LVEF ≤40% and either
Aldosterone
Inhibitor of
diabetes or heart failure
• Not recommended for hyperkalemia or severe renal
dysfunction
Antman EM, Hand M, Armstrong PW, et al. Circulation. 2008;117:296-329.
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Complications of ACS
• Arrhythmias
• Hemodynamic disturbances
• Mechanical damage
• Recurrent chest pain
• Ischemic stroke
• Deep venous thrombosis
• Pulmonary embolism
Arrhythmias: Fibrillation and
Tachycardia
Common early after STEMI
• Ventricular fibrillation
– Uncoordinated signals; no effective pumping
– Occurs in 3%–5% of patients after STEMI; may cause sudden death if
not treated effectively
• Tachycardia
– Abnormally fast heart rate (>100 bpm)
• Treatment
– Countershock in hemodynamically significant arrhythmias
(cardioversion vs.. defibrillation, dependent on rhythm and whether a
pulse is present), possibly with medical therapy
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Arrhythmias: Bradycardias and Conduction
Abnormalities
Arrhythmia
Description
Incidence
Bradycardia
Abnormally slow heart rate
30%–40% of MIassociated
arrhythmias
Heart block
Impaired signal transmission of
signals between the atria and the
ventricles
6%–14% of STEMI
Intraventricular
conduction delay
More common in
inferior infarctions
Delayed signal transmission through 1 10%–20% of STEMI
or both bundle branches
• Related to the extent of ischemia and infarction
• Treatment: observation, pharmacologic therapy (atropine), or electronic pacing
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Heart Failure
Failure to pump blood with normal efficiency
• Low cardiac output
– Usually estimated using the left ventricular ejection fraction
(LVEF)
• Pulmonary edema/congestion
– Fluid in the lungs because of increased ventricular pressure
• Cardiogenic shock
– Inability to supply enough blood to support organ function
– Medical emergency requiring prompt treatment
Other Complications of ACS
•
Weakened necrotic tissue may fail
•
Papillary muscles: mitral regurgitation
•
Septal defect: opening between the left and right
ventricles
•
Free wall rupture: opening in the heart wall, causes
tamponade
Right ventricular infarction
•
Necrosis may affect the right ventricle
Recurrent chest pain after STEMI
•
Recurrent ischemia or infarction
•
Pericarditis
Ischemic stroke
•
0.75%–1.2% of MIs; especially with atrial fibrillation
Deep venous thrombosis and
pulmonary embolism
•
Bed rest and heart failure promote thrombus
formation in the veins; thrombi may cause
pulmonary embolism
Mechanical damage
Ongoing In-hospital Risk Assessment
Goals
• Monitor disease status and the risk of worsening
• Update prognosis
• Determine:
– Intensity of therapy
– Need for coronary angiography
– Need for electrophysiology studies and possible
intracardiac defibrillator placement
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Major Determinants of Risk after MI
• LVEF
• Quantity of potentially ischemic myocardium
• Susceptibility to ventricular arrhythmia
Antman E, Morrow DA. ST-segment elevation myocardial infarction: management. In: Bonow RO, Mann
DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1111-1177.
LVEF and Risk after MI
LVEF
• Most important risk factor
• Fraction of blood ejected from the left ventricle with each
heartbeat
• Related to the amount of viable myocardium
• Measured with echocardiography and/or other techniques
• LVEF <40% indicates high risk
Antman E, Morrow DA. ST-segment elevation myocardial infarction: management. In: Bonow RO, Mann
DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1111-1177.
Potential Extent of Ischemia and Risk after MI
Quantity of potentially ischemic myocardium
• Assessed with noninvasive risk stratification testing
– Exercise or pharmacologic stress testing
– Echocardiography or myocardial perfusion imaging
• Identify provocable ischemia
• Determine exercise recommendations
Antman E, Morrow DA. ST-segment elevation myocardial infarction: management. In: Bonow RO, Mann
DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1111-1177.
Arrhythmias and Risk after MI
Susceptibility to ventricular arrhythmia
• Potentially fatal complication
• No clearly beneficial screening tests
• Prophylactic therapy with antiarrhythmic agents other
than beta-blockers has been harmful in clinical trials and
is not recommended
Antman E, Morrow DA. ST-segment elevation myocardial infarction: management. In: Bonow RO, Mann
DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1111-1177.
Hospital Discharge
Goals
•
•
Prepare the patient for normal activities to the extent possible
Re-evaluate the plan of care, particularly lifestyle and risk-factor modification
Length of stay
•
If no major complications
– Typically 24–72 hours for UA/NSTEMI
– Typically 5–6 days for STEMI
•
With complications
– Stable for several days, appropriate workup, appropriate response to therapy
A “teachable moment”
•
Education and counseling on physical activity, risk-factor reduction, medication
adherence
Antman E, Morrow DA. ST-segment elevation myocardial infarction: management. In: Bonow RO, Mann
DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1111-1177.
Cannon CP, Braunwald E. Unstable angina and non-ST elevation myocardial infarction. In: Bonow RO,
Mann DL, Zipes P, et al, eds. Braunwald's Heart Disease. 9th ed. Philadelphia, PA: Elsevier Saunders;
2011:1178-1209.
Key Cardiologist Concerns
• Effective transition to primary care
• Adherence
– Medication regimen
– Lifestyle changes
– Follow-up
• Patient education
• Physician communication
Villanueva T. J Hosp Med. 2010 Sep;5 Suppl 4:S8-14.
Postdischarge Care and Secondary Prevention
• Goal: reduce the risk of recurrent ACS
• Essential for all patients
• Aggressively manage risk
– Lifestyle changes
– Pharmaceutical therapy
• Address other health concerns
Anderson JL, Adams CD, Antman EM, et al. Circulation. 2007;116:e148-e304.
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Pharmaceutical Therapy for Secondary
Prevention
• Antiplatelet agents
• Anticoagulants (warfarin and novel agents)
• Beta-blockers and calcium channel blockers
• RAAS inhibitors
• Other antihypertensive agents
• Statins and other lipid management agents
Follow-up and Rehabilitation
Cardiac rehabilitation is recommended for most patients
Follow-up
•
•
•
•
Assess cardiovascular symptoms and risk
Review and reinforce adherence to medication and lifestyle changes
Assess psychosocial status
Educate patient and caregivers on management of recurrent ACS
Return to work and other activities
• 63%–94% of patients who have had an MI return to work
Antman EM, Anbe DT, Armstrong PW, et al. Circulation. 2004;110:e82-292.
Thank You