Non st elevation myocardial infarction and unstable angina

NON-ST ELEVATION MYOCARDIAL INFARCTION

AND UNSTABLE ANGINA

Grerk Sutamtewagul, M.D.

June 2012

Outline

Definition Pathophysiology Clinical Presentation Risk Stratification Early Hospital Care

Medical treatmentTreatment strategy

Long Term Management

Definition

Unstable angina and Non-ST Elevation Myocardial Infarction

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)

NSTEMI

Approximately 2/3 of patient with UA have elevated cardiac serum markers – thus the diagnosis of NSTEMI

Pathophysiology

Unstable anginaand Non-ST Elevation Myocardial Infarction

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)

Pathophysiologic process

3. Severe coronary luminal narrowing Atherosclerosis Post-PCI restenosis

4. Inflammation

5. Secondary unstable angina to tachycardia, fever, hypotension, anemia

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

Plaque rupture and thrombosis

Platelet activation and aggregation Secondary hemostasis

InitiationAmplificationPropagation

Clinical Presentation

Unstable anginaand Non-ST Elevation Myocardial Infarction

Clinical Examination

Largely unremarkable Signs of large fraction ischemia:

DiaphoresisPale, cool skinSinus tachycardiaThird or forth heart soundBasilar ralesHypotension

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)

ST segment

51 yo F with CP+SOB

5 hrs later

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.

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.

Risk Stratification

Unstable anginaand Non-ST Elevation Myocardial Infarction

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.

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.

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.

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.

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]

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.

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)

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.

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

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

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.

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)

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].

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.

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]

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.

Emerging Biomarkers in ACS

Integrated Approach

TIMI risk score GRACE risk score

Prognostic tools with high discriminatory ability using baseline variables which are parts of routine medical evaluation.

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.

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.

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.

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.

GRACE risk score

Data from Global Registry of Acute Coronary Events (GRACE) with 15,007 subjects across the spectrum of ACS 9 predictive variables.

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.

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.

Early Hospital Management

Unstable anginaand Non-ST Elevation Myocardial Infarction

Early hospital care

General and anti-ischemic therapy Antiplatelet therapy Anticoagulant therapy ACEI or ARB Treatment strategies: initial conservative

vs early invasive

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)

Anti-ischemic therapy

NITRATESEndothelium-independent vasodilators (via

G protein and cAMP)Coronary vasodilationArteriolar and venous dilation reduced

myocardial afterload, preload, and wall stress

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.

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]

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.

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

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.

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)

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

Antiplatelets

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).

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.

Aspirin

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)

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)

ADP antagonist

ThienopyridinesTiclopidineClopidogrelPrasugrelElinogrel

Non-thienopyridinesTigagrelorCangrelor

ADP antagonist

Cattaneo M. New P2Y(12) inhibitors. Circulation. 2010 Jan 5;121(1):171-9.

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.

ADP antagonist

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.

Figure 1. Cardiovascular death, MI, or stroke for entire study.

Fox K A et al. Circulation 2004;110:1202-1208

Copyright © American Heart Association

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.

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.

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).

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

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

Strategies for initiation of clopidogrel therapy Start at presentation Start immediately after PCI

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

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

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

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

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.

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

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.

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

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.

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

ADP antagonist

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

Prasugrel

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

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

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

Ticagrelor

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.

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.

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

Glycoprotein IIb/IIIa inhibitors Abciximab in UA/NSTEMI pts whom

early conservative strategy was planned no benefit and higher early mortality

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]

Other antiplatelets

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)

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)

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)

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)

Anticoagulants

Heparin Low-molecular-weight heparin Fondaparinux Direct thrombin inhibitors Direct Xa inhibitors

Heparin

Activating Antithrombin (previously known as antithrombin III)

Accelerate the inhibition of Thrombin and FXa

Heparin

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

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

Low-Molecular-Weight Heparin

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.

Fondaparinux

Synthetic analogue of the antithrombin-binding sequence found in heparin and LMWH.

Indirectly inhibit FXa via antithrombin

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

Direct thrombin inhibitors Univalent DTI

AgatrobanApixabanDabigatran

Bivalent DTIHirudin (leech)LepirudinBivalirudin (Angiomax)

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).

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

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.

Treatment Strategies

Unstable anginaand Non-ST Elevation Myocardial Infarction

Treatment Strategies

Early invasive strategy Conservative approach

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

Treatment Strategies

To date, comparisons of these 2 strategies have been studied in 10 randomized trials. 4 trials – no difference6 trials – favor invasive strategies

Treatment Strategies

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

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)

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.

• 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

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

Other therapies

Inhibition of Renin-Angiotensin-Aldosterone SystemAngiotensin-converting enzyme inhibitorsAngiotensin receptor blockers

Lipid-lowering therapyHydroxymethylglutaryl coA reductase

inhibitors (statins)

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.

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)

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.

Long-term secondary prevention

Unstable anginaand Non-ST Elevation Myocardial Infarction

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

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

Statins

Statins should be given in pts post-UA/NSTEMI before discharge, regardless of baseline LDL-C. (class I, LOE A)

European Society of Cardiology guideline comparison

Unstable anginaand Non-ST Elevation Myocardial Infarction

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.

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.

ESC 2011 vs ACC/AHA 2011 Indication for invasive strategy

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.