Acute Coronary Syndromes Chapter 28

1
Acute Coronary SyndromesChapter 28
Chapter 18

• Pharmacotherapy A Pathophysiologic Approach
• The McGraw-Hill Companies

2
Abbreviations

• ACC American College of Cardiology
• ACE angiotensin-converting enzyme
• ACS acute coronary syndrome
• ACUITY Acute Catheterization and Urgent
  Intervention Triage
• Strategy
• ADP adenosine diphosphate
• AHA American Heart Association
• ARB angiotensin receptor blocker
• ASPECT Antithrombotics in Secondary Prevention
  of
• Events in Coronary Thrombosis
• CK creatine kinase

3
Abbreviations

• CABG coronary artery bypass graft
• CHD coronary heart disease
• CVD cardiovascular disease
• DHA docosahexaenoic acid
• ECG electrocardiogram
• EF ejection fraction
• EPA eicosapentaenoic acid
• EPHESUS Eplerenone Post-Acute Myocardial
  Infarction
• Heart Failure Efficacy and Survival Study
• ExTRACT Enoxaparin versus Unfractionated Heparin
  with
• Fibrinolysis for ST-elevation Myocardial
  Infarction

4
Abbreviations

• HIT Heparin induced thrombocytopenia
• ICH intracranial hemorrhage
• INR international normalized ratio
• IV intravenous
• LDL low-density lipoprotein
• LMWH low-molecular-weight heparin
• LV left ventricular
• LVEF left ventricular ejection fraction
• MADIT Multicenter Automatic Defibrillator
  Implantation Trial
• MB myocardial band
• MI myocardial infarction

5
Abbreviations

• NCEP National Cholesterol Education Program
• NICE-SUGAR Intensive Versus Conventional Glucose
  Control
• in Critically Ill Patients Trial
• NRMI National Registry of Myocardial Infarction
• NSAID nonsteroidal antiinflammatory drug
• NSTE nonST-segment elevation
• OASIS Organization for the Assessment of
  Strategies for
• Ischemic Syndromes
• OAT Occluded Artery Trial
• PCI percutaneous coronary intervention
• TIMI Thrombolysis in Myocardial Infarction
• UFH unfractionated heparin
• WARIS Warfarin Re-Infarction Study

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Recommendations Evidence

• Strength of recommendations
• A good, B moderate, C poor
• Quality of evidence
• 1 more than 1 properly randomized, controlled
  trial
• 2 at least 1 well-designed clinical trial with
  randomization from cohort or case-controlled
  analytic studies or dramatic results from
  uncontrolled experiments or subgroup analyses
• 3 opinions of respected authorities, based on
  clinical experience, descriptive studies, or
  reports of expert communities

7
Key Concepts

• Acute coronary syndromes (ACS) typically caused
  by atherosclerotic plaque rupture subsequent
  clot formation
• Risk-stratify patients with suspected ACS based
  on ECG, symptoms lab tests
• Early reperfusion with PCI or fibrinolytic
  recommended for patients with ST-segment
  elevation myocardial infarction (STEMI)

8
Key Concepts

• High-risk NSTE (non ST-segment elevation) ACS
  patients should have early coronary angiography
  revascularization
• ACS patients should also receive early therapy
  with intranasal oxygen, aspirin, clopidogrel,
  nitroglycerin, ß-blocker an anticoagulant
• MI patients should receive indefinite therapy
  with ASA, ß-blocker, ACE inhibitor or ARB
• Selected patients should receive statin,
  clopidogrel or anticoagulation

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Epidemiology

• 1.5 million American experience an ACS every year
• 220,000 of those will die of an MI
• Chest discomfort 2nd most frequent reason for ED
  visits
• CHD leading cause of premature disability in the
  US
• 2007 cost of CHD 151.6 billion

Anderson JL, Adams CD, Antman EM, et al. ACC/AHA
2007, Guidelines for the management of patients
with unstable angina/non ST-elevation myocardial
infarction A report of the ACC/AHA Task Force on
Practice Guidelines Circulation
2007116803877.
American Heart Association. Heart Disease and
Stroke Statistics2007, Update. Dallas, TX
American Heart Association, 2007.
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Epidemiology

• In hospital death rates
• STE ACS 4.6
• NSTE ACS 2.2
• Lower mortality rates for patients treated with
  reperfusion therapy (fibrinolytics or PCI)
• Mortality rates higher in women elderly patients

American Heart Association. Heart Disease and
Stroke Statistics2007, Update. Dallas, TX
American Heart Association, 2007.
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Etiology

• Atherosclerosis starts early in life
• Inflammation plays key role
• Several factors contribute to evolution of
  endothelial dysfunction formation of fatty
  streaks arteries that lead to atherosclerotic
  plaques

• HTN
• age
• male gender
• tobacco use

• DM
• obesity
• dyslipidemias

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Pathophysiology

• ACSs result from myocardial ischemia due to
  imbalance between myocardial O2 demand supply
• usually due to occluded coronary artery thrombus
• STEMI, NSTEMI, unstable angina fall under this
  heading
• unstable angina does not produce detectable
  biochemical marker levels

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Comparison of ACSs
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
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CAD Causes
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
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Plaque Rupture Clot Formation

• gt 90 of ACSs caused by rupture or erosion of an
  atherosclerotic plaque
• Plaques likely to rupture
• those that occlude lt 50 of the lumen
• eccentric shape
• thin fibrous cap with large fatty core
• Clots form on top of ruptured plaques partially
  or fully occlude the artery lumen
• Exposure of collagen tissue factor from the
  plaque induces platelet adhesion activation
• promotes release of vasoactive substances

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Atheroma Production
A normal muscular artery. The adventitia, or
outermost layer of the artery, consists
principally of recognizable fibroblasts
intermixed with smooth muscle cells loosely
arranged between bundles of collagen and
surrounded by proteoglycans. It is usually
separated from the media by a discontinuous sheet
of elastic tissue, the external elastic lamina.
B platelet aggregates, or microthrombi, form as
a result of adherence of the platelets to the
exposed subendothelial connective tissue.
Platelets that adhere to the connective tissue
release granules whose constituents may gain
entry into the arterial wall. Platelet factors
thus interact with plasma constituents in the
artery wall and may stimulate events shown in the
next illustration C smooth muscle cells migrate
from the media into the intima and actively
multiply within the intima. Endothelial cells
regenerate in an attempt to re-cover the exposed
intima, which thickens rapidly owing to smooth
muscle proliferation and formation of new
connective tissue.
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Plaque Rupture Clot Formation

• Platelet activation changes on platelet GP
  IIb/IIIa receptors lead to formation of fibrin
  bridges
• inclusion of many platelets creates white clots
• more common in NTSE ACS
• incomplete artery occlusion
• Coagulation cascade activated fibrin traps RBCs
• clots have red appearance
• more common in STE ACS
• more likely to completely occlude vessels
• Myocardial ischemia can result from microthrombi
  embolization lead to necrosis

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Ventricular Remodeling

• Changes in size, shape function of the left
  ventricle (LV)
• results in HF
• ACE inhibitors, ARBs, ß-blockers, aldosterone
  antagonists
• slow down or reverse remodeling
• improve chance of survival

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Complications

• Cardiogenic shock
• 5 to 6 of STEMI patients
• 2 of NSTE ACS
• mortality rate 60
• Others
• heart failure
• valve dysfunction
• arrhythmias
• heart block

• pericardititis
• stroke
• venous thromboembolism
• LV free-wall rupture

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Symptoms

• Midline anterior anginal chest pain
• Severe new-onset angina
• Increasing angina gt 20 minutes
• Pain may radiate
• left arm
• jaw
• back
• Nausea, vomiting, diaphoresis, shortness of
  breath
• Women, diabetics, elderly patients may have
  atypical or no symptoms

21
Electrocardiogram

• 12-lead ECG should be done within 10 min of ED
  arrival
• Key findings indicating myocardial damage
• ST-segment elevation
• ST-segment depression
• T-wave inversion

22
Biochemical Markers

• Evaluate troponin CK MB to confirm MI
• released in response to myocardial necrosis
• 3 measurements taken over the 1st 12 to 24 hrs
• MI diagnosis
• gt 1 one troponin value greater than MI decision
  limit set by lab
• or
• 2 CK MB values greater than MI decision limit set
  by lab

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NSTEMI
STEMI
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STEMI
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Risk Stratification

• Treat STEMI patients as fast as possible
• NST ACS patients stratified based on clinical
  presentation, lab findings
• Risk categories
• high
• medium
• low
• TIMI Thrombolysis In Myocardial Infarction
• Treatment based on TIMI score

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aTroponin I, troponin T,
or creatinine kinase MB greater than the MI
detection limit.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
29
Treatment Goals

• Restore blood flow to prevent infarct expansion
  MI
• Prevent death, complications
• Prevent coronary artery reocclusion
• Relieve ischemic chest discomfort
• Maintain normoglycemia

30
2006 American College of Cardiology/American
Heart Association STE and NSTE MI Performance
Measures
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
31
2006 American College of Cardiology/American
Heart Association STE and NSTE MI Performance
Measures
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
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Nonpharmacologic Therapy

• STEMI patients should receive either fibrinolysis
  or primary PCI within 3 hrs of symptom onset
• PCI preferred treatment in capable centers
• High risk NST ACS patients may undergo PCI or
  CABG
• early invasive strategy

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Primary PCI

• A meta-analysis comparing fibrinolysis with PCI
  indicated lower mortality rate in PCI patients
• PCI opens arteries better than fibrinolytics
• reduces risk of major bleeding, intracranial
  hemorrhage (ICH)
• better side effect profile
• Door-to-balloon time
• time of hospital presentation to time occluded
  artery is opened should be lt 90 min

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Additional Testing

• Echocardiogram to determine LV function
• LV function best predictor of mortality after MI
• LVEF lt 40 higher risk of death
• Implantable cardioverter defibrillator (ICD) may
  be placed in patients with ventricular
  tachycardias
• May perform stress testing in moderate or low
  risk patients to diagnose CAD
• Draw fasting lipid panel

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Early Pharmacotherapy for ACS

• Intranasal oxygen (if O2 saturation lt 90)
• Sublingual NTG (IV if indicated)
• ß-blocker (PO)
• Anticoagulation
• UFH, enoxaparin, etc.
• Morphine can be given for refractory anginal pain
• Fibrinolytics in STE ACS only

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(ACE, angiotensin-converting enzyme ACS, acute
coronary syndrome ARB, angiotensin receptor
blocker CABG, coronary artery bypass graft
surgery IV, intravenous NTG, nitroglycerin
PCI, percutaneous coronary intervention SC,
subcutaneous SL, sublingual UFH, unfractionated
heparin.) aAlthough recommended by the 2004
American College of Cardiology and American Heart
Association practice guidelines, no dose
recommendation is given. bSee Table 184 for
dosing and specific types of patients who should
not receive enoxaparin or IV NTG.)
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Pharmacotherapy for STE ACS

• In the ED
• sublingual or IV NTG
• ASA
• ß-blocker
• unfractionated heparin (UFH) or enoxaparin
• morphine PRN
• fibrinolysis

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Pharmacotherapy for STE ACS

• All patients at discharge
• ASA
• ß-blocker
• statin/lipid lowering therapy
• ACE inhibitor or ARB
• Select patients
• aldosterone antagonists
• clopidogrel
• warfarin

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Pharmacotherapy for NSTE ACS

• Similar to STE ACS treatment with a few
  exceptions
• fibrinolytic therapy contraindicated
• GP IIb/IIIa receptor blockers administered to
  high-risk patients
• no established quality performance measures for
  STE ACS patients with unstable angina

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Fibrinolytics

• Indicated in STEMI patients who present within 12
  hours of symptom onset have gt 1 mm of STE on
  EKG (Class 1)
• not indicated in NSTE ACS
• CI in patients with high bleeding risk
• Fibrinolytic therapy controversial in patients gt
  75 yr

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Contraindications to Fibrinolysis

• Absolute contraindications
• active internal bleeding (not including menses)
• previous intracranial hemorrhage at any time
• ischemic stroke within 3 months
• intracranial neoplasm
• structural vascular lesion (e.g., arteriovenous
  malformation)
• suspected aortic dissection
• significant closed head or facial trauma within 3
  months

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Contraindications to Fibrinolysis

• Relative contraindications
• uncontrolled HTN (BP gt 180/110 mm Hg)
• ischemic stroke gt 3 months
• dementia
• intracranial pathology
• current anticoagulant use
• bleeding diathesis
• traumatic or prolonged CPR (gt 10 min)
• major surgery (lt 3 wks)

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Contraindications to Fibrinolysis

• Relative contraindications
• noncompressible vascular puncture
• recent liver biopsy
• carotid artery puncture
• recent internal bleeding (within 2 to 4 wks)
• for streptokinase administration, previous
  streptokinase use (gt 5 days) or prior allergic
  reaction
• pregnancy
• active peptic ulcer
• history of severe, chronic, poorly controlled HTN

45
Comparison of Fibrinolytic Agents
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
46
Fibrinolytics

• Fibrin specific agents (alteplase, tenecteplase,
  reteplase) preferred over non-fibrin specific
  agents (streptokinase)
• studies show lower mortality for fibrin specific
  agents
• Alteplase most indications difficult to dose
  bolus followed by weight based infusion
• Tenecteplase single weight-based dose
• Reteplase 2 fixed doses (no weight adjustment)

47
Fibrinolytics

• ICH major bleeding most serious side effects
• ICH rates higher in fibrin specific agents
• systemic bleeding other than ICH higher with
  streptokinase
• Door-to-needle time lt 30 min
• quality performance measure

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Anti-platelet Agents

• ASA
• Thienopyridines
• clopidogrel preferred agent
• ticlopidine associated with neutropenia
  requires close CBC monitoring during 1st 3 months
  of treatment
• GP IIa/IIIa Receptor Inhibitors
• abciximab
• eptifibatide
• tirofiban

49
Aspirin (ASA)

• Preferred anti-platelet agent for treatment for
  all ACSs (Class I)
• Start during 1st 24 hrs of hospitalization
• Studies show lower 35-day vascular mortality
  compared to placebo
• Dosing 162 to 325 mg PO loading dose, then 75
  to 162 mg PO daily
• maintenance dose should be higher in patients
  with intracoronary stent for the 1st 1 to 6
  months depending on type of stent
• Continue indefinitely

50
Aspirin (ASA)

• Irreversible inhibition of platelet
  cycloxygenase-1 (COX-1)
• may have anti-inflammatory effects
• Monitor for bleeding
• Contraindications
• hypersensitivity
• active bleeding
• severe bleeding risk

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Clopidogrel

• Alternative for patients with ASA allergy (Class
  1)
• STE ACS
• added to ASA in patients undergoing primary PCI
  (Class 1)
• based on current data, clopidogrel should be
  given to patients treated by fibrinolytics or
  those receiving no revascularization with
  PCI/CABG (Class 1)
• NSTE ACS
• recommended for most patients in combination with
  ASA for up to 12 months (Class 1)

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Clopidogrel

• Blocks ADP2Y12 receptors on platelets
• prevents fibrin binding
• Dosing
• 300 to 600 mg PO loading dose
• followed by 75 mg PO daily
• Duration of therapy depends on type of stent

53
Clopidogrel

• Contraindications
• hypersensitivity
• active bleeding
• severe bleeding risk
• Adverse effects
• bleeding
• nausea
• vomiting
• diarrhea

54
GP IIb/IIIa Receptor Inhibitors

• STE ACS
• abciximab indicated for patients undergoing 1
  PCI in combination with ASA, clopidogrel, UFH
  (Class 2a)
• eptifibatide also FDA approved for this
  indication (Class 2b)
• use in patients not undergoing PCI not
  recommended

55
GP IIb/IIIa Receptor Inhibitors

• NSTE ACS
• tirofiban or eptifibatide recommended for
  high-risk patients not undergoing
  revascularization or patients with continued
  ischemia despite treatment with ASA, clopidogrel
  an anticoagulant (Class 2a)
• abcixicmab or eptifibatide recommended for
  patients undergoing PCI (Class 1)

56
GP IIb/IIIa Receptor Inhibitors

• Prevents cross linking of platelets through
  inhibition of GP IIb/IIIa receptors
• May help with early opening of coronary arteries
• Contraindications
• active bleeding
• thrombocytopenia
• history of stroke
• Adverse effects
• bleeding
• immune mediated thrombocytopenia

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Clinical Controversies

• Early up stream administration of a GP IIb/IIIa
  inhibitor vs delayed selective therapy at time of
  PCI in NSTE ACS patients
• A recent study showed no statistical difference
  in ischemic events but more bleeding events when
  the drug was given prior to angiography
• short administration times
• statistical power may not have been sufficient
• Timing of GP IIb/IIIa administration in NSTE ACS
  patients undergoing angiography remains
  controversial

Stone GW, Bertrand ME, Moses JW, et al. Routine
upstream initiation vs. deferred selective use of
glycoprotein IIb/IIa inhibitors in acute coronary
syndromes The ACUITY Timing Trial.
JAMA.2007297591-602.
61
Anticoagulants

• Heparins
• unfractionated heparin (UFH)
• low molecular weight heparin (LMWH)
• enoxaparin, dalteparin
• Factor X-A Inhibitor
• fondaparinux
• Direct Thrombin Inhibitors
• bivalirudin reversible binding
• lepirudin irreversible binding
• argatroban reversible binding

62
Unfractionated Heparin (UFH)

• 1st line anticoagulant for STE ACS PCI
• administered with a fibrin selective fibrinolytic
  (Class 1)
• NSTE ACS
• preferred anticoagulant following angiography in
  patients undergoing CABG (Class 1)
• option for patients undergoing planned early
  angiography revascularization (Class 1)
• may be used in patients in whom an initial
  conservative strategy is planned (Class 1)

63
Unfractionated Heparin (UFH)

• Binds antithrombin inhibits clotting factors Xa
  IIa (thrombin)
• IV bolus followed by infusion, adjust according
  to aPTT or antifactor Xa levels
• Can be used in patients with renal dysfunction
• Continue 48 hrs in patients who will be on
  warfarin, otherwise discontinue immediately after
  PCI

64
Heparin
65
Unfractionated Heparin (UFH)

• Contraindications
• history of heparin induced thrombocytopenia (HIT)
• active bleeding
• severe bleeding risk
• recent stroke
• Adverse effects
• bleeding
• HIT

66
Enoxaparin

• STEMI
• not studied in primary PCI (Class 2b as
  alternative to UFH)
• NSTEMI ACS
• option for patients undergoing planned early
  angiography and revascularization (Class 2a)
• UFH recommended over enoxaparin or fondaparinux
  (Class 1b)
• may be used in patients in whom an initial
  conservative strategy is planned (Class 1)
• fondaparinux recommended over enoxaparin (Class
  1a)
• enoxaparin recommended over UFH (Class 1b)

Schünemann HJ, Hirsh J, Guyatt G, et al.
Executive Summary American College of Chest
Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition). Chest. 200813371-109.
67
Enoxaparin

• Binds antithrombin, inhibits factors Xa IIa
• ExTRACT trial (Enoxaparin versus Unfractionated
  Heparin with Fibrinolysis for ST-Elevation MI)
  n20,506
• enoxaparin 30 mg IV bolus, 1 mg/kg SQ 15 min
  later then every 12 hr (dose ? for age gt 75 yr,
  renal dysfunction)
• UFH 60 units/kg IV bolus (maximum 4000 units)
  followed by 12 units/kg/hr infusion with
  adjustments to maintain aPPT 1.5 to 2.0 times the
  control value
• 17 risk reduction for death or nonfatal MI in
  patients on enoxaparin compared to UFH

Antman EM, Morrow DA, McCabe CH, et al.
Enoxaparin versus unfractionated heparin with
fibrinolysis for ST-elevation myocardial
infarction. N Engl J Med 200635414771488.
68
Enoxaparin

• Shorter chain length compared to UFH
• more predictable effects
• Contraindications
• active bleeding, severe bleeding risk
• history of HIT
• recent stroke
• CrCl lt 15 ml/min
• avoid in CABG patients
• Dose 1 mg/kg every 12 hrs (renal adjustment
  required)
• Adverse effects bleeding HIT (lesser extent
  than UFH)

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Fondaparinux

• Inhibits factor Xa
• less likely to cause HIT than UFH, LMWH
• STE ACS
• alternative to UFH in patients not undergoing
  reperfusion (Class 1) or receiving fibrinolytics
  (Class 2b)
• not recommended for use alone in 1 PCI (Class 1a)

Schünemann HJ, Hirsh J, Guyatt G, et al.
Executive Summary American College of Chest
Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition). Chest. 200813371-109.
70
Fondaparinux

• NSTE ACS
• option for patients undergoing planned early
  angiography revascularization with PCI
• option for patients in whom an initial
  conservative strategy is planned
• preferred agent for patients with high risk for
  bleeding (Class 1)

71
Direct Thrombin Inhibitors

• NSTE ACS
• bivalirudin option in patients undergoing
  planned early angiography revascularization
  (Class 1)
• Inhibit clot-bound circulating thrombin
• Does not bind plasma proteins
• More predictable response than UFH
• Antiplatelet activity

72
Direct Thrombin Inhibitors

• ACUITY trial (Acute Catheterization and Urgent
  Intervention Triage StrategY)
• Moderate to high risk patients with ACS
  undergoing invasive intervention (n13,819)
  evaluated after 1 year
• 3 groups
• bivalirudin
• bivalirudin GP IIb/IIIa inhibitor
• heparin/enoxaparin GP IIb/IIIa inhibitor
• Outcomes death, MI, unplanned revascularization

White HD, Ohman EM, Lincoff AM, et al. Safety and
efficacy of bivalirudin with and without
glycoprotein IIb/IIIa inhibitors in patients with
acute coronary syndromes undergoing percutaneous
coronary intervention 1-year results from the
ACUITY (Acute Catheterization and Urgent
Intervention Triage strategy) trial. J Am Coll
Cardio. 200852(10)807-14.
73
Direct Thrombin Inhibitors

• ACUITY results
• no difference in incidence of ischemic events or
  mortality at 1 year between the 3 regimens
• 43 relative risk reduction for major bleeding in
  bivalirudin monotherapy group at 30 days compared
  to UFH or enoxaparin GP IIb/IIIa inhibitor
• bilvalirudin alone can replace UFH or enoxaparin
  GP IIb/IIIa inhibitor in moderate to high risk
  ACS patients undergoing PCI

White HD, Ohman EM, Lincoff AM, et al. Safety and
efficacy of bivalirudin with and without
glycoprotein IIb/IIIa inhibitors in patients with
acute coronary syndromes undergoing percutaneous
coronary intervention 1-year results from the
ACUITY (Acute Catheterization and Urgent
Intervention Triage strategy) trial. J Am Coll
Cardio. 200852(10)807-14.
74
Nitrates

• Given to both STE NSTE ACS patients ischemic
  chest pain relief (Class 1)
• No mortality benefit in acute MI
• Symptom relief only
• Dose 0.4 mg SL tab every 5 min up to 3 times
• if chest pain persists, IV nitroglycerin may be
  indicated for 24 hr after relief of ischemia

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Nitrates

• Promote release of nitric oxide producing
  vasodilation myocardial ischemia relief
• venodilation lowers myocardial O2 demand
  preload
• arterial vasodilation may lower BP
• Contraindicated in patients with recent
  phoshodiesterase-5 inhibitor use
• Adverse effects

• headache
• flushing

• hypotension
• tachycardia

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ß-Blockers

• Cardioselective
• atenolol, betaxolol, bisoprolol, metoprolol,
  nebivolol
• Nonselective
• nadolol, propranolol, timolol
• Mixed a- ß-blockers
• carvedilol, labetolol
• IV only
• esmolol

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ß-Blockers

• Should be given early to STE ACS NSTE ACS
  patients in the absence of contraindications
  (Class 1)
• continue indefinitely
• quality care indicator for MI patients
• IV ß-blockers only given to hemodynamically
  stable patients without signs/symptoms of
  decompensated HF
• risk of cardiogenic shock

78
ß-Blockers

• Competitive blockade of myocardium ß1 receptors
• reduce
• HR
• myocardial contractility
• BP
• myocardial O2 demand
• Improve ventricular filling time artery
  perfusion

79
ß-Blockers

• Adverse effects
• hypotension
• acute HF
• bradycardia
• heart block
• may mask hypoglycemia symptoms
• use short acting agents in patients with
  bronchospastic pulmonary disease

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Calcium Channel Blockers

• Dihydropyridines
• amlodipine
• felodipine
• nifedipine
• nicardipine
• clevidipine
• Non-dihydropyridines (negative inotropic effects)
• verapamil
• diltiazem

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Calcium Channel Blockers

• Use in STE NSTE ACS reserved for patients with
  contraindications to ß-blockers (Class 1)
• Inhibit Ca2 influx to myocardial vascular
  smooth muscle cells
• cause vasodilation
• Non-dihydropyridines have additional antiischemic
  effects
• slow HR via AV node conduction
• Little benefit shown beyond symptom relief
• Negative inotropic effects may worsen outcomes

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2MI Prevention Goals

• Control modifiable CHD risk factors
• Prevent development of systolic HF
• Prevent recurrent MI, stroke
• Prevent death, including sudden cardiac death

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2MI Prevention

• Following STEMI/NSTEMI, treat patients
  indefinitely with ASA, ß-blocker, ACEI
• NTG for ischemic chest discomfort
• many patients should also receive clopidogrel
• Annual influenza vaccination
• Warfarin in select patients
• controversial
• Statins used in most patients
• Glycemic control is important

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Modifiable Risk Factors

• Smoking cessation
• HTN control
• Weight loss
• Glycemic control
• Dyslipidemia treatment

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Aspirin

• Decreases risk of death, recurrent MI, stroke
  following MI
• Quality care indicator for MI patients
• Continue indefinitely unless contraindicated
• Dose 75 to 81 mg
• patients with stents 325 mg for 1 to 12 months
• Monitor for bleeding
• especially when used in combination with warfarin
  or clopidogrel

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Clopidogrel

• Decreases risk of death, MI, stroke in NSTE ACS
  patients
• clopidogrel aspirin for up to 1 yr
• STEMI patients who did not have revascularization
  may receive 14 to 28 days of clopidogrel
• Continue for at least 1 yr if possible in
  patients with stent placement
• Monitoring
• bleeding, rash, GI upset

87
Clinical Controversy

• Interactions between clopidogrel PPIs
• Retrospective cohort study (n8205)
• 5244 patients taking clopidogrel PPI after
  hospitalization for ACS 2961 did not receive a
  PPI
• Clopidogrel PPI associated with higher risk of
  death or rehospitalization for ACS compared with
  clopidogrel without PPI
• adjusted hazard ratio, 1.27 95 CI, 1.10-1.46
• FDA issued a safety bulletin, additional studies
  in progress

Ho PM, Maddox TM, Wang L, et al. Risk of adverse
outcomes associated with concomitant use of
clopidogrel and proton pump inhibitors following
acute coronary syndrome. JAMA. 2009301(9)937-44.
88
Warfarin

• Consider anticoagulation in select patients
  following ACS
• LV thrombus
• history of thromboembolic events
• chronic atrial fibrillation
• Routine warfarin treatment should not be used in
  HF patients in normal sinus rhythm without
  another indication
• Reduces risk of death, MI, stroke
• Doubles major bleeding risk

89
Warfarin

• INR monitoring required
• Many drug food interactions
• Addition of warfarin to aspirin clopidogrel
  further increases risk for bleeding
• Not currently recommended by any professional
  organization except select situations

90
Clinical Controversies

• Combination ASA, clopidogrel, warfarin not well
  studied
• Used in patients with stents patients with
  indications for anticoagulation along with
  history of low EF MI
• Requires close monitoring
• Lower INR target (2 to 2.5) may be appropriate

91
ACE Inhibitors

• Start in all MI patients to reduce mortality,
  decrease reinfarction prevent HF (Class 1)
• prevent cardiac remodeling
• start PO ACE inhibitor within 24 hrs of MI
• Rx for ACE inhibitor or ARB at hospital discharge
  is a quality care indicator
• Continue indefinitely in patients with LVEF lt
  40, HTN, DM, CKD

92
Angiotensin Receptor Blockers

• Candesartan valsartan shown to improve clinical
  outcomes in HF patients (Class 1 for patients
  with ACE inhibitor intolerance)
• alternatives for patients with low EF following
  MI unable to take ACE inhibitors
• class effect?
• Little to no evidence ARBs are useful in
  diastolic HF
• Lower incidence of cough angioedema compared to
  ACE inhibitors

93
Aldosterone Antagonists

• Eplerenone PostAcute Myocardial Infarction Heart
  Failure Efficacy and SUrvival Study (EPHESUS)
• Showed reduced mortality from sudden death, HF,
  MI in patients treated with eplerenone compared
  to placebo
• Consider eplerenone or spironolactone within 2
  weeks following MI in certain patients (Class 1)
• those already receiving an ACE inhibitor with EF
  lt 40 HF symptoms or DM

Pitt B, Remme W, Zannad F, et al. Eplerenone, a
selective aldosterone blocker in patients with
left ventricular dysfunction after myocardial
infarction. N Engl J Med 200334813091321.
94
Aldosterone Antagonists

• Aldosterone causes vascular myocardial
  fibrosis, endothelial dysfunction, HTN, LV
  hypertrophy, electrolyte abnormalities,
  arrhythmias
• Monitor K
• especially patients with renal dysfunction
• Spironolactone can cause gynecomastia, sexual
  dysfunction, menstrual irregularities
• eplerenone less likely to cause adverse reactions

95
Lipid Lowering Agents

• HMG-CoA reductase inhibitors (statins)
• simvastatin, atorvastatin, lovastatin,
  fluvastatin, pravastatin, rosuvastatin
• ezetimbe
• fenofibrate, gemfibrozil (drug interaction with
  statins)
• niacin
• fish oil

96
Lipid Lowering Agents

• Patients with CAD have LDL cholesterol goal lt 100
  mg/dL
• LDL cholesterol lt 70 mg/dL optional goal
• All ACS patients should receive a statin
• Statins have anti-inflammatory anti-thrombotic
  properties
• lipid lowering therapy at discharge is a quality
  care indicator
• Consider a fibrate or niacin in patients with a
  low HDL (lt 40 mg/dL) or high triglycerides (gt
  200 mg/dL)

97
Glycemic Control

• Hyperglycemia associated with increased morbidity
  mortality in hospitalized patients
• NICE-SUGAR (Normoglycemia in Intensive Care
  Evaluation-Survival Using Glucose Algorithm
  Regulation)
• n6104
• blood glucose target lt 180 mg/dL for critically
  ill patients resulted in lower mortality than
  intensive glucose control (target 81 to 108 mg/dL)

The NICE-SUGAR Study Investigators. The
Normoglycemia in Intensive Care
Evaluation-Survival Using Glucose Alogorithm
Regulation (NICE-SUGAR). NEJM. 20093601283-1297
98
Monitoring

• Parameters for monitoring efficacy of
  nonpharmacologic pharmacotherapy for STE NSTE
  ACS are similar
• relief of ischemic discomfort
• return of ECG changes to baseline
• absence or resolution of HF signs

99
Monitoring
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
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Monitoring
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
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Monitoring
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
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Acknowledgements

• Prepared By Mandy Brown, Pharm.D.
• Series Editor April Casselman, Pharm.D.
• Editor-in-Chief Robert L. Talbert, Pharm.D.,
  FCCP, BCPS, FAHA
• Chapter Authors Sarah A. Spinler, Pharm.D., BCPS
  (AQ Cardiology)
• Simon De Denus, MSc, BPharm
• Section Editor Robert L. Talbert, Pharm.D.,
  FCCP, BCPS, FAHA