Non st elevation myocardial infarction and unstable angina
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NON-ST ELEVATION MYOCARDIAL INFARCTION
AND UNSTABLE ANGINA
Grerk Sutamtewagul, M.D.
June 2012
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Outline
Definition Pathophysiology Clinical Presentation Risk Stratification Early Hospital Care
Medical treatmentTreatment strategy
Long Term Management
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Definition
Unstable angina and Non-ST Elevation Myocardial Infarction
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Unstable angina
Angina pectoris or equivalent type of ischemic discomfort with at least 1/3 of the following
1. Occurring at rest and lasting > 20 mins
2. New onset, severe symptom
3. Crescendo pattern (increasing in severity, duration, or frequency)
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NSTEMI
Approximately 2/3 of patient with UA have elevated cardiac serum markers – thus the diagnosis of NSTEMI
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Pathophysiology
Unstable anginaand Non-ST Elevation Myocardial Infarction
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Pathophysiologic process
1. Plaque rupture or erosion with superimposed thrombus*
2. Dynamic obstructionSpasm of epicardial artery (Prinzmetal)Constriction of small intramural arteriesLocal vasoconstrictors (e.g. TXA2) released
from plateletsDysfunction of coronary endotheliumAdrenergic stimuli (cold, cocaine)
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Pathophysiologic process
3. Severe coronary luminal narrowing Atherosclerosis Post-PCI restenosis
4. Inflammation
5. Secondary unstable angina to tachycardia, fever, hypotension, anemia
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Plaque rupture and thrombosis
Platelet activation and aggregationExposure to subendothelial matrix (tissue factor,
collagen)Platelet adhesion (GP Ib-vWF and GP VI-
collagen)Platelet activation:
○ Morphology change (smooth spiculated)○ Degranulation (TXA2, serotonin, etc.)
○ GP IIb/IIIa receptor expression and enhancementPlatelet aggregation (GP IIb/IIIa – fibrinogen)
Secondary hemostasis
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Plaque rupture and thrombosis
Platelet activation and aggregation Secondary hemostasis
InitiationAmplificationPropagation
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Clinical Presentation
Unstable anginaand Non-ST Elevation Myocardial Infarction
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Clinical Examination
Largely unremarkable Signs of large fraction ischemia:
DiaphoresisPale, cool skinSinus tachycardiaThird or forth heart soundBasilar ralesHypotension
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Electrocardiography
EKG abnormality found in 50% of patients with UA/NSTEMI
ST depression (>0.1 mV or >0.05 mV if prior EKG available)
Transient ST elevation (10%, poor prognosis)
T wave change (sensitive but not specific unless > 0.3 mV)
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ST segment
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51 yo F with CP+SOB
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5 hrs later
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Markers of Cardiac Necrosis CK-MB Troponin T, Troponin I Higher level associates with worse
prognosis. Patients with UA/NSTEMI and troponin
elevation but no apparent CAD on angiography had significantly worse prognosis than those who have troponin negative1.1. Braunwald E, Lakkis N; TACTICS-TIMI-18 Investigators. Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: a TACTICS-TIMI-18 substudy. J Am Coll Cardiol. 2005 Jan 4;45(1):19-24. Erratum in: J Am Coll Cardiol. 2005 Jun 7;45(11):1911.
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Laboratory testing
Serum lipid panel – treatable risk factor Total Cholesterol and HDL-C fall by as
much as 30-40% in 24 hrs after UA/NSTEMI or STEMI.
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Risk Stratification
Unstable anginaand Non-ST Elevation Myocardial Infarction
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High-risk clinical subgroups Age
PURSUIT trial: univariate relationship between age and 30-day mortality was curvilinear with reflection at around 65 years in UA/NSTEMI.
Boersma E et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators.Circulation. 2000 Jun 6;101(22):2557-67.
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High-risk clinical subgroups Gender
Women with ACS tend to have more traditional risk factors confounded
Women usually presents with more atypical features delay in diagnosis
Women with presumed ACS have less severe epicardial CAD.
Multivariate model: gender was not associated with cardiovascular outcomes2.
2 Hochman JS, et al. Outcome and profile of women and men presenting with acute coronary syndromes: a report from TIMI IIIB. TIMI Investigators. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol. 1997 Jul;30(1):141-8.
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High-risk clinical subgroups Diabetes
Potent risk indicatorIncrease in oxidative stress
proatherogenicRisk of first MI in diabetics without prior MI is
approximately equal to recurrent MI in non-diabetics who had prior MI*.
* Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.
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Mortality comparison
Haffner SM, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.
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High-risk clinical subgroups Diabetes
1.5 to 2.0-fold higher rate of death and cardiac ischemic events for patients with NSTEMI (GUSTO IIb, PRISM-PLUS, FRISC II, TACTIC-TIMI 18, GUSTO IV-ACS)
Data across 11 TIMI trials: ○ 30-day mortality adj OR 1.78 [1.24-2.56]○ 1-yr mortality adj HR 1.65 [1.30-2.10]
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High-risk clinical subgroups Smoking
Smoker’s Paradox○ Current smokers tend to have lower rates of
death and ischemic events than nonsmokers.Multivariate analysis: smoking is not a
significant independent prognostic factor.*
* Barbash GI, et al. Evaluation of paradoxic beneficial effects of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: mechanism of the "smoker's paradox" from the GUSTO-I trial, with angiographic insights. Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol. 1995 Nov 1;26(5):1222-9.
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High-risk clinical subgroups Peripheral vascular disease
Independent risk factor for death and ischemic complications in patients with UA-NSTEMI even after adjustment for traditional risk factors. (OPUS-TIMI 16, PURSUIT study)
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High-risk clinical subgroups Prior aspirin use
Multiple studies have confirmed that patients with prior aspirin use are at increased risk.
Present of aspirin-resistant platelet-rish thrombi.
Aspirin resistance may be associated with increased risk of death and cardiovascular complications.
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High-risk clinical subgroups Severity of angina
Worse prognosis with○ Multiple episodes of angina in the past 24 hrs○ Angina at rest○ Post-infarction angina
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High-risk clinical subgroups Physical examination
Physical exam suggestive of LV dysfunction is more commonly seen in STEMI.
Higher Killip class (≥2) significant underlying CAD higher mortality
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Holmes DR Jr et al. Cardiogenic shock in patients with acute ischemic syndromes with and without ST-segment elevation. Circulation. 1999 Nov 16;100(20):2067-73.
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High-risk clinical subgroups Electrocardiogram
Admission ECG is one of the most useful and powerful predictors of adverse outcomes.
ST depression is associated with○ Worse in-hospital prognosis○ Greater complexity and extent of the lesion
ST depression as little as 0.05 mV had ≈ 2 fold death or MI at 30 days and 1 year [TIMI III Registry]
T wave inversion is generally not assoc with worse prognosis (except deep TWI lateral leads)
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High-risk clinical subgroups Markers of necrosis
Blood samples should be obtained at least 6 to 9 hours after the onset of symptoms
There is a quantitative relationship between the magnitude of CK-MB, Troponin I and risk of death [PURSUIT, TIMI IIIb].
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Troponin I and mortality
Antman EM, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996 Oct 31;335(18):1342-9.
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What should be the appropriate cut point of troponin assay?
Consensus panels recommend cut point at 99th percentile from a cohort of healthy individuals and coefficient of variation less than 10% (for study precision).
Trials of UA-NSTEMI supported the prognostic importance of “low-level” troponin elevation even below such cut point [data from TACTIC-TIMI 18]
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Death, MI, ACS vs Troponin
Morrow DA, et al; TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA. 2001 Nov 21;286(19):2405-12.
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Emerging Biomarkers in ACS
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Integrated Approach
TIMI risk score GRACE risk score
Prognostic tools with high discriminatory ability using baseline variables which are parts of routine medical evaluation.
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TIMI Risk Score for UA/NSTEMI
Data from 1957 patients who were randomized to the UFH arm of TIMI 11B trial (UA/NSTEMI only) Multivariated logistic regression analysis 7 independent predictors.
TRS for UA/NSTEMI has been validated in many cohorts, including ESSENCE and TACTICS-TIMI 18.
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TIMI Risk Score for UA/NSTEMI
Antman EM et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000 Aug 16;284(7):835-42.
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TIMI Risk Score for UA/NSTEMI
Antman EM et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000 Aug 16;284(7):835-42.
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TIMI Risk Score for UA/NSTEMI
Antman EM et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA. 2000 Aug 16;284(7):835-42.
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GRACE risk score
Data from Global Registry of Acute Coronary Events (GRACE) with 15,007 subjects across the spectrum of ACS 9 predictive variables.
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Comparison of TRS for UA/NSTEMI and GRACE score
Retrospective analysis and prospective observational studies suggest that GRACE score has greater prognostic discrimination compared to TRS for UA/NSTEMI.
One retrospective analysis found no difference between GRACE score and TRS for STEMI.
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TRS vs GRACE score
Ramsay G, Podogrodzka M, McClure C, Fox KA. Risk prediction in patients presenting with suspected cardiac pain: the GRACE and TIMI risk scores versus clinical evaluation. QJM. 2007 Jan;100(1):11-8. Epub 2006 Dec 15.
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Early Hospital Management
Unstable anginaand Non-ST Elevation Myocardial Infarction
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Early hospital care
General and anti-ischemic therapy Antiplatelet therapy Anticoagulant therapy ACEI or ARB Treatment strategies: initial conservative
vs early invasive
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General Measures Patient at medium-high risk should be admitted to
intensive or intermediate cardiac care unit + ECG monitoring
Bed rest Oxygen for SaO2 less than 90%, respiratory
distress, other high-risk features for hypoxemia (Class I), or all patient with UA/NSTEMI in the first 6 hours (Class
IIa)
Anti-ischemic therapy: Nitrate, beta-blocker Intravenous Morphine
for uncontrolled CP despite NTG. (Class IIa)
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Anti-ischemic therapy
NITRATESEndothelium-independent vasodilators (via
G protein and cAMP)Coronary vasodilationArteriolar and venous dilation reduced
myocardial afterload, preload, and wall stress
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Anti-ischemic therapy
NITRATES0.4 mg NTG Sublingual q5mins x 30.3-0.6 mg NTG Buccal spray q5mins x 3If symptoms persist, IV NTG start at 5-10
μg/min, increase by 10 μg/min q3-5mins until relief of symptoms.
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Anti-ischemic therapy
NITRATESIV NTG should not be increased if it will
preclude the use of beta-blocker or ACEI.Contraindications: Hypotension, use of
sidenafil or related phosphodiesterase-5 inhibitors within previous 12-48 hours, HR<50, or HR >100 in the absence of symptomatic HF or RV infarction
8-10 hours of nitrate-free interval to avoid the development of tolerance
No effect on mortality [ISIS-4]
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Beta-blockers Reduce subsequent MI or recurrent
ischemia† and rate of VF‡, reduction in mortality in early placebo-controlled trials
Reduction in mortality in 21st century is less clear.Chen et al∏. 45,852 subjects - Metoprolol vs
Placebo in MI: Death OR 0.99, [0.92-1.05] [COMMIT trial]
† Gottlieb SO, et al. Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized, double-blind, placebo-controlled trial. Circulation. 1986 Feb;73(2):331-7.‡ Yusuf S, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985 Mar-Apr;27(5):335-71.∏ Chen ZM, et al; COMMIT collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1622-32.
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Beta-blockers
Oral beta-blocker should be initiated within the first 24 hours (Class I) for pt without contraindication and ≥ 1 of the following:Signs of HFLow output stateAt risk for cardiogenic shock
○ Age>70, SBP<120mmHg, HR<60 or >110Relative contraindications: PR >240ms, 2nd or
3rd degree heart block, active asthma, Reactive airway
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Calcium channel blocker Calcium channel blockers
vasodilatory effects, reduce blood pressure, slow heart rate and reduce myocardial contractility
Reduce recurrent MI in early studiesNon-dihydropyridine (Verapamil, Diltiazem) should
be used.Short-acting dihydropyridine CCB (e.g.
Nifedipine), which accelerate HR, has been shown to be harmful when it is not coadministered with beta-blocker.
Long-acting dihydropyridine CCB is safe for stable CAD.
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Calcium channel blocker
In whom beta blockers are contraindicated, a nondihydropyridine CCB should be given as initial therapy. (Class I)in the absence of significant LV dysfunction
For recurrent ischemia after beta blocker and nitrates have been fully used, oral long-acting nondihydropyridine CCB can be used (Class IIa)
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Antiplatelet Therapy
Platelets play a major role in pathogenesis of UA/NSTEMI.
Accordingly, antiplatelet therapy plays a central role in management.
Antiplatelets:AspirinADP receptor (P2Y12) antagonist
Glycoprotein IIb/IIIa (αIIbβ3) inhibitor
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Antiplatelets
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Aspirin
Irreversibly acetylates platelet cyclooxygenase 1 (COX-1) decrease synthesis and release of Thromboxane A2 (TXA2), a major platelet activator.
Antiplatelet effect lasts for lifetime of the platelets (7-10 days).
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Aspirin Several trials have demonstrated clear
beneficial effects of ASA in UA/NSTEMI. Approximately 25% reduction in death or
MI Efficacy is not dose-dependent. CURRENT-OASIS 7 compared high-dose
(300-325 mg) versus low-dose (75-100 mg) aspirin daily after a loading dose No difference in death, MI, stroke, major bleeding in 30 days.†
† Mehta SR, et al. CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010 Sep 2;363(10):930-42. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585.
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Aspirin
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Aspirin
Aspirin resistance2-8% of patients have limited anti-platelet
effectLead to worse cardiovascular outcomeOften related to poor complianceConcomitant use of ibuprofen (reversible
COX-1 inhibitor – competitively bound to COX-1)
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Aspirin
ASA should be administered to patients with UA/NSTEMI as soon as possible after hospital presentation and continued indefinitely in patients who tolerate it. (Class I, LOE A)
Clopidogrel can be used if the patients who are unable to take aspirin. (Class I, LOE B)
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ADP antagonist
ThienopyridinesTiclopidineClopidogrelPrasugrelElinogrel
Non-thienopyridinesTigagrelorCangrelor
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ADP antagonist
Cattaneo M. New P2Y(12) inhibitors. Circulation. 2010 Jan 5;121(1):171-9.
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Thienopyridines
Prodrugs Oxidation by P-450 system in the liver Active metabolites irreversibly inhibit the
binding of ADP to platelet P2Y12 receptor inhibit platelet aggregation.
Ticlopidine is the first thienopyridines. Its use was limited by bleeding complication, neutropenia, and risk of TTP.
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ADP antagonist
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Clopidogrel Absorption 85% Hydrolyzed P-450 oxidation
(mainly cytochrome 2C19) As effective as ticlopidine for prevention of stent
thrombosis but less bleeding complication. CURE trial: 12,562 UA/NSTEMI patients ASA +
heparin + clopidogrel or placebo 20% reduction in cardiovascular death, MI or stroke in all groups (high-low risk, PCI-medical-CABG). Benefit seen from first 24 hours and extended through the 1-year period of the study.
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Figure 1. Cardiovascular death, MI, or stroke for entire study.
Fox K A et al. Circulation 2004;110:1202-1208
Copyright © American Heart Association
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Clopidogrel before PCI
Clopidogrel given before PCI29% reduction in cardiovascular death or MIBenefit even without concomitant GP IIb/IIIa
inhibitor
Sabatine MS,et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005 Sep 14;294(10):1224-32. Epub 2005 Sep 4.
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CLARITY-TIMI 28
Sabatine MS,et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005 Sep 14;294(10):1224-32. Epub 2005 Sep 4.
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Clopidogrel before CABG
In patient undergoing CABG, clopidogrel given within 5 days before surgery is associated with major bleeding complication and longer hospital stay (not statistically significant).
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Figure 3. Major bleeding (point estimates and CIs) for study as a whole.
Fox K A et al. Circulation 2004;110:1202-1208
Copyright © American Heart Association
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TABLE 4
The time interval between study drug discontinuation and early CABG surgery in relation to bleeding frequency
Life threatenting or other major bleeds within 7 days of CABG surgery
Placebo Clopidogrel RR 95% CI
% %Day of CABG 6/119 5 9/110 8.2 1.62 0.60-4.411 day prior to CABG 11/139 7.9 11/99 11.1 1.4 0.63-3.112 days prior to CABG 7/95 7.4 12/118 10.2 1.38 0.57-3.373 days prior to CABG 3/73 4.1 5/54 9.3 2.25 0.56-9.024 days prior to CABG 3/50 6.0 5/55 9.1 1.52 0.38-6.02≥5 days prior to CABG 24/454 5.3 20/456 4.4 0.83 0.46-1.48
Fox K A et al. Circulation 2004;110:1202-1208
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Strategies for initiation of clopidogrel therapy Start at presentation Start immediately after PCI
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Strategies for initiation of clopidogrel therapy Start at presentation
Reducing ischemic event before PCIIncrease bleeding in pt who undergo CABG
Start immediately after PCIDecrease bleeding, blood transfusion,
immediate post-op death
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Strategies for initiation of clopidogrel therapy Overall benefit-to-risk ratio from major
randomized studies favors early initiation of clopidogrel.
Biancari, et al. J Thorac Cardiovasc Surg, Mar 2012
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Loading dose
Initial loading dose decrease the time achieving target level.
Clopidogrel 75 mg/day 3-5 days Clopidogrel 300 mg loading 4-6 hrs Clopidogrel 600 mg loading 2 hrs
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Loading dose
Clopidogrel 600 mg vs 300 mg loading Lower rate of major cardiovascular event
[ARMYDA-2]
No difference in cardiovascular death, MI, or stroke [CURRENT-OASIS 7]
Review of literature: Decrease major adverse cardiovascular
eventsMarginally decrease all-cause mortalitySlightly increase bleeding risk
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Nijjer SS, et al. Quantitative comparison of clopidogrel 600mg, prasugrel and ticagrelor, against clopidogrel300mg on major adverse cardiovascular events and bleeding in coronary stenting: Synthesis of CURRENT-OASIS-7, TRITON-TIMI-38 and PLATO. Int J Cardiol. 2012 Jul 12;158(2):181-5. Epub 2012 Jan 10.
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Clopidogrel hyporesponsiveness
Common among DiabeticsObesityAdvanced ageGenetic polymorphism in cytochrome P450
(esp. CYP2C19 - *C2 allele)○ 1/3 of Whites, more frequent in Asians○ Related with adverse outcome and in stent
thrombosis
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Clopidogrel and PPI
Proton-pump inhibitors (PPI) are often prescribed prophylactically to prevent GI bleeding due to dual-antiplatelet therapy.
Some PPIs inhibit CYP2C19: omeprazole, lansoprazole, rabeprazole but not pantoprazole
Some observational studies reported adverse cardiovascular outcome with PPI-clopidogrel-ASA.
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Clopidogrel and PPI
2 randomized trials: PRINCIPLE TIMI-44 and TRITON TIMI-38 PPI treatment attenuated the
pharmacodynamic effect of clopidogrel.PPI treatment did not affect the clinical
outcome. The finding was true for all PPIs including omeprazole and pantoprazole.
COGENT study: omeprazole vs placeboNo difference cardiovascular events HR
0.99 [0.68-1.44] but obvious benefit in GIB
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Clopidogrel and PPI
Bhatt DL, COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010 Nov 11;363(20):1909-17. Epub 2010 Oct 6.
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Prasugrel
Prodrug Active metabolite is an irreversible
inhibitor of the platelet P2Y12 receptor. CYP2C19 is not the major enzyme
Decrease interaction with PPICan be use in clopidogrel hyporesponders
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ADP antagonist
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Prasugrel
TRITON-TIMI 38 trial13,608 pts with ACS (10,074 with
UA/NSTEMI) in whom PCI was planned.Loading 60 mg 10 mg dailyCompared to clopidogrel 300 75 mgReduce cardiovascular death, MI, and
stroke by 19% HR 0.81 [0.73-0.90]Decrease in stent thrombosis by 52% HR
0.48 p<0.0001
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Prasugrel
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Prasugrel TRITON-TIMI 38 trial
More common in serious bleedingRisk of bleeding was especially higher in
○ Elderly (>75 yo)○ Body weight < 60 kg
Prasugrel is contraindicated in patient with history of stroke or TIA.
Prasugrel use should be strictly followed the study protocol of TRITON-TIMI 38 design.Diagnostic catheterization first planned PCI
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Ticagrelor
Non-thienopyridine Not require P450 for activation Reversibly block P2Y12 platelet receptor Ticagrelor and its active metabolite are
excreted into the bile. Rapid onset (30 mins) Shorter half-life
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Ticagrelor
PLATO trial18,624 pts;15,381 (62%) had UA/NSTEMICompare Ticagrelor (90 mg BID) with
Clopidogrel (300 or 600 75 mg daily)16% Reduction in composite cardiovascular
death, MI, and stroke22% Reduction in total mortality
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Ticagrelor
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Ticagrelor
PLATO trialNo difference in total major bleeding but
significantly higher non-CABG major bleeding
Should be started at ER If necessary, it could be stopped and
CABG could be carried out 48-72 hrs later.
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Glycoprotein IIb/IIIa inhibitors Abciximab (ReoPro) mAb – only prior
PCI Eptifibatide (Integrilin) Tirofiban (Aggrastat)
Bind GP IIb/IIIa (αIIbβ3) thus prevent platelet aggregation caused by all types of stimuli.
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Glycoprotein IIb/IIIa inhibitors Intravenous bolus followed by
continuous infusion Receptor blocking activity and
associated bleeding risk subside promptly after discontinuation.
Several trials confirm the benefit for cardiovascular death, MI
Also benefit even on the background of clopidogrel pretreatment
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Glycoprotein IIb/IIIa inhibitors Abciximab in UA/NSTEMI pts whom
early conservative strategy was planned no benefit and higher early mortality
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Glycoprotein IIb/IIIa inhibitors Timing of GP IIb/IIIa inhibition
Starting at the time of presentation orUse just before or during PCI
No difference in benefit Risk of major bleeding is higher with
longer infusion group. [EARLY ACS trial]
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Other antiplatelets
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Early hospital care antiplatelet therapy Pts with definite UA/NSTEMI at medium
or high risk, initial invasive strategy ASA plus one of the followingBefore PCI
○ Clopidogrel (Class I, LOE B)
○ An IV GPIIb/IIIa inhibitor (Class I, LOE A)
At PCI○ Clopidogrel if not started○ Prasugrel (Class I, LOE B)
○ An IV GPIIb/IIIa inhibitor (Class I, LOE A)
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Early hospital care antiplatelet therapy Pts with initial conservative strategy
Clopidogrel loading dose followed by daily maintenance dose [added to ASA and anticoagulant therapy]
Administered for at least 1 monthIdeally up to 1 year (Class I, LOE B)
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Early hospital care antiplatelet therapy Loading dose of thienopyridines:
Clopidogrel 300-600 mg as early as possible before or at the time of PCI (Class I, LOE A)
Prasugrel 60 mg no later than 1 hr after PCI once coronary anatomy is defined, decide to do PCI (Class I, LOE B)
Maintenance dose at least 12 monthsClopidogrel 75 mg dailyPrasugrel 10 mg daily (Class I, LOE B)
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Early hospital care antiplatelet therapy UA/NSTEMI, early invasive;
Clopidogrel 600 mg loading doseFollowed by 150 mg daily for 6 daysThen 75 mg daily In patient not high risk of bleeding (Class IIb,
LOE B)
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Anticoagulants
Heparin Low-molecular-weight heparin Fondaparinux Direct thrombin inhibitors Direct Xa inhibitors
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Heparin
Activating Antithrombin (previously known as antithrombin III)
Accelerate the inhibition of Thrombin and FXa
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Heparin
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Heparin
Unfractionated heparin (UFH) has been a cornerstone of therapy for patients with UA/NSTEMI.
Goal aPTT of 50-75 sec or 1.5-2.5x 33% reduction in death or MI comparing
UFH+ASA vs ASA alone
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Low-Molecular-Weight Heparin
Compare to UFHLMWH has greater anti-FXa activity more
effective in decreasing synthesis of thrombinLower rate of thrombocytopeniaHigher bioavailability subcut adminLess binding to plasma protein more
consistent effect no need for monitoring aPTT
In case of bleeding, reversal of protamine is less effective.
Need renal adjustment
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Low-Molecular-Weight Heparin
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Low-Molecular-Weight Heparin
LMWH was found to be non-inferior to UFH.
Enoxaparin provides significant benefit over UFH in patients with UA/NSTEMI who are managed conservatively and receive at least 48 hrs of anticoagulation but not in patients managed invasively.
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Fondaparinux
Synthetic analogue of the antithrombin-binding sequence found in heparin and LMWH.
Indirectly inhibit FXa via antithrombin
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Fondaparinux
OASIS-5 trial20,078 pts with high-risk UA/NSTEMILow dose fondaparinux (2.5 mg sc daily) vs
standard dose enoxaparinNo difference in 9-day death, MI Lower 30-day mortality (2.9% vs 3.5%)Significantly reduce the rate of major
bleeding3x increase in catheter related thrombi
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Direct thrombin inhibitors Univalent DTI
AgatrobanApixabanDabigatran
Bivalent DTIHirudin (leech)LepirudinBivalirudin (Angiomax)
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Direct thrombin inhibitors Not require antithrombin Able to inhibit clot-bound thrombin Not interact with plasma protein Not cause thrombocytopenia
FDA approved for treatment of HIT (lepirudin and agatroban)
Recent FDA approval of bivalirudin for PCI (but not approved for HIT).
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Bivalirudin Angiomax Binds reversibly to thrombin, cleaved by
thrombin No need to monitor ACT except in case of
renal insufficiency ACUITY trial
13,819 pts with UA/NSTEMI, managed with early invasive strategy
UFH or enoxaparin / GPIIb/IIIa / bivalirudinNo difference in efficacy (death, MI)Lower rate of bleeding in bivalirudin alone
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Additional Management of antiplatelet and anticoagulation
UA/NSTEMI; initial conservative; low risk stress testIndefinite ASA (Class I, LOE A)
Clopidogrel at least 1 month, ideally 1 yr (Class I, LOE B)
UFH for 48 hrs (Class I, LOE A)
Enoxaparin or Fondaparinux for the duration of hospitalization, up to 8 days, then discontinue.
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Treatment Strategies
Unstable anginaand Non-ST Elevation Myocardial Infarction
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Treatment Strategies
Early invasive strategy Conservative approach
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Treatment Strategies
Early invasive strategyRoutine early cardiac catheterization
followed by PCI, CABG, or continuing medical therapy
Conservative approachInitial medical management and
catheterization reserved for patients with recurrent ischemia either at rest or on a non-invasive test
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Treatment Strategies
To date, comparisons of these 2 strategies have been studied in 10 randomized trials. 4 trials – no difference6 trials – favor invasive strategies
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Treatment Strategies
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Indications for invasive vs conservative management
Early invasive strategy has been shown to benefit in patients withST-segment changesPositive troponinRecurrent ischemiaEvidence of CHFAll men and high-risk women
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Initial invasive vs initial conservative Early invasive strategy is indicated in
patients withRefractory anginaHemodynamic or electrical instability (Class I,
LOE B)
Elevated risk for clinical events* (Class I, LOE A)
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Diagnosis of UA/NSTEMI is Likely or Definite
ASA (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE: B)
Select Management Strategy
Initial Conservative Strategy or Unknown Invasive Strategy†
Initiate anticoagulant therapy (Class I, LOE: A)Acceptable options include• Enoxaparin or UFH (Class I, LOE: A)• Fondaparinux (Class I, LOE: B)*• Enoxaparin or fondaparinux preferred over UFH(Class IIa, LOE: B)
Initiate clopidogrel (Class I, LOE: B)
Initiate anticoagulant therapy (Class I, LOE: A)*Acceptable options include• Enoxaparin or UFH (Class I, LOE: A)• Bivalirudin (Class I, LOE: B)
CABG:Maintenance ASA(Class I, LOE: A)
MedicalTherapy: D/C GP IIb/IIIa inhibitors if begun and giveclopidogrel perconservativestrategy
Precatheterization: Add second antiplatelet agent (Class I, LOE: A)‡
• Clopidogrel (Class I, LOE: B) or• GP IIb/IIIa inhibitor (Class I, LOE: A)• (IV eptifibatide or tirofiban preferred)Next step per triage decision at angiography
PCI: Class I: • Clopidogrel (if not begun precatheterization) (LOE: A) or• Prasugrel (LOE: B) or• Selectively, a GP IIb/IIIa inhibitor (if not begun precatheterization) (LOE: A)
Wright RS, et al. J Am Coll Cardiol. 2011;57(19):1920-59.
*If fondaparinux is used with an invasive strategy (Class I, LOE: B), it must be coadministered with another anticoagulant with Factor IIa activity, i.e., UFH.)
†Timing of invasive strategy generally is assumed to be 4 to 48 hours. If immediate angiography is selected, see STEMI guidelines.
‡Precatheterization triple antiplatelet therapy (ASA, clopidogrel, GP inhibitors) is a Class IIb, LOE: B rec for selected high-risk patients.
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• Cont aspirin (Class I, LOE: A)
• DC clopidogrel 5 to 7 d prior to elective CABG (Class I, LOE: B)
• DC IV GP IIb/IIIa 4 h prior to CABG (Class I, LOE: B)
• Cont UFH (Class I, LOE: B); DC enoxaparin 12 to 24 h prior to CABG; DC fondaparinux 24 h prior to CABG; DC bivalirudin 3 h prior to CABG. Dose with UFH per institutional practice (Class I, LOE: B)
• Cont aspirin (Class I, LOE A)
• LD of clopidogrel if not given pre angio (Class I, LOE: A)
&• IV GP IIb/IIIa if not started
pre angio (Class I, LOE: A)
• DC ACT after PCI for uncomplicated cases (Class I, LOE: B)
• Cont aspirin (Class I, LOE: A)• LD of clopidogrel if not
given pre angio (Class I, LOE A)*• DC IV GP IIb/IIIa after
at least 12 h if started pre angio (Class I, LOE: B)
• Cont IV UFH for at least 48 h (Class I, LOE: A) or enoxaparin or fondaparinux for dur of hosp (LOE: A); either DC bivalirudin or cont at a dose of 0.25 mg/kg/hr for up to 72 h at physician‘s discretion (Class I, LOE: B)
Antiplatelet and ACT at physician’s discretion (Class I, LOE: C)
No significant obstructive
CAD on angiography
CAD on angiography
Medical therapyPCICABG
Select Post Angiography Management Strategy
Dx Angiography
Management after Diagnostic Angiography in Patients with UA/NSTEMI
Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 9. ACT = anticoagulation therapy; LOE = level of evidence.
G H
I
J
F
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Cardiac cath
CAD No Discharge from protocol
Yes
Left main disease Yes CABG
No
1- or 2- Vessel
Disease
3- or 2-vessel disease with proximal LAD involvement
LV dysfunction or treated diabetes*
No
PCI or CABG
Medial Therapy,
PCI or CABG
Yes CABG
*There is conflicting information about these patients. Most consider CABG to be preferable to PCI. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 20.
Revascularization Strategy in UA/NSTEMI
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Other therapies
Inhibition of Renin-Angiotensin-Aldosterone SystemAngiotensin-converting enzyme inhibitorsAngiotensin receptor blockers
Lipid-lowering therapyHydroxymethylglutaryl coA reductase
inhibitors (statins)
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ACEI/ARB
Large trials have shown a 0.5% absolute mortality benefit of early ACEI (within 24 hours) in acute MI.
No benefit in patients without ST elevation. [ISIS-4]
Long-term use prevents ischemic events and mortality.
ARB can be used in pts who cannot tolerate ACEI.
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ACEI/ARB An ACE inhibitor should be administered orally
within the first 24 h to UA/NSTEMI patients with Pulmonary congestion or LV ejection fraction (LVEF) less than or equal to 0.40Not or known contraindications (class I, LOE A)
ARB can be used instead in pts who are intolerant to ACEI. (class I, LOE A)
ACE inhibitor (or ARB if not tolerate ACEI) is reasonable in pts without LV dysfunction. (class IIa, LOE A)
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Lipid-lowering therapy
Long-term treatment with statin has shown benefit in pts after acute MI and UA/NSTEMI.
PROVE IT-TIMI 22Intensive lipid-lowering therapy with
Atorvastatin 80 mg resulted in 16% reduction in MI, death or rehospitalization for ACS compared with moderate dose of pravastatin (40 mg).
Suggest Early initiation of statin.
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Long-term secondary prevention
Unstable anginaand Non-ST Elevation Myocardial Infarction
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Long-term secondary prevention Six classes of therapies that have improved
outcomes after UA/NSTEMI in large randomized trials:Intensive LDL-C reduction with high dose statinsACEI or ARBBeta blockerLow dose ASA plus a P2Y12 inhibitor for at least
a yearSmoking cessation programsExercise-based cardiac rehabilitation
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Long-Term Antithrombotic Therapy at Hospital Discharge after UA/NSTEMI
Medical Therapy
without Stent
Bare Metal Stent Group
Drug Eluting Stent Group
aspirin 162 to 325 mg/d for at least 1 month, then 75 to 162
mg/d indefinitely (Class I, LOE: A)
&Clopidogrel 75 mg/d for at least 1 month and up to 1
year (Class I, LOE:B)
Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B)
Continue with dual antiplatelet therapy as
above
Yes
No
Indication for Anticoagulation?
aspirin 75 to 162 mg/d indefinitely (Class I, LOE:
A)
&
Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up to 1 year (Class
I, LOE: B)
aspirin 162 to 325 mg/d for at least 3 to 6 months,
then 75 to 162 mg/d indefinitely
(Class I, LOE: A)
&
Clopidogrel 75 mg/d for at least 1 year (Class I, LOE:
B)
Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 11. INR = international normalized ratio; LOE = level of evidence.
UA/NSTEMI Patient Groups at Discharge
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Statins
Statins should be given in pts post-UA/NSTEMI before discharge, regardless of baseline LDL-C. (class I, LOE A)
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European Society of Cardiology guideline comparison
Unstable anginaand Non-ST Elevation Myocardial Infarction
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ESC 2011 vs ACC/AHA 2011 Antiplatelets (Class I)
Ticagrelor (180 90 mg BID) for all mod-high risk regardless of treatment strategy.
Prasugrel (60 10 mg daily) is recommended for P2Y12 naïve patients (esp DM) in whom coronary anatomy is known.
Clopidogrel (300 (or 600 if invasive) 75 mg daily) is recommended for pts who cannot receive ticagrelor or prasugrel.
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ESC 2011 vs ACC/AHA 2011 Anticoagulants (Class I)
Fondaparinux (2.5 mg sc daily) is recommended as having the most favourable efficacy-safety profile.○ Single bolus UFH at PCI
Enoxaparin (1mg/kg BID) is recommended when fondaparinux is not available.
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ESC 2011 vs ACC/AHA 2011 Indication for invasive strategy
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Key Reference Bonow, RO. Braunwald’s Heart Disease: A textbook of
cardiovascular medicine: Chapter 56 Unstable angina and
Non-ST elevation myocardial infarction. 9th edition. Mar
2011.
Wright RS, et al. 2011 ACCF/AHA focused update
incorporated into the ACC/AHA2007 Guidelines for the
Management of Patients with Unstable Angina/Non-ST-
Elevation Myocardial Infarction. J Am Coll Cardiol. 2011
May 10;57(19):e215-367.
Updated ESC Guidelines for managing patients with
suspected non-ST-elevation acute coronary syndromes.
Eur Heart J. 2011 Dec;32(23):2909-10.