UA/NSTEMI Guidelines

Dr. Sajeer K.T

Senior Resident

Dept. of Cardiology

Definition UA/NSTEMI

Electrocardiographic ST segment depression or

prominent T wave inversion

and/or

Positive biomarkers of necrosis (troponin )

In the absence of ST segment elevation

In an appropriate clinical setting ( chest discomfort or

anginal equivalent)

ACC/AHA Task force on practice guidelines

• 2007

• 2011 focused updates

Risk stratificationEarly hospital careConservative management strategy Invasive management strategy

Risk stratification

• Diagnostic evaluation:

• Assesses the risk that a pt with UA/NSTEMI has for MI or death during next few weeks.

• Focuses on history

Physical findings

ECG findings

Biomarkers of cardiac injury (Cardiac specificTroponin)

TIMI score

•Age ≥ 65 years

•At least 3 risk factors for CAD

•Prior coronary stenosis of ≥ 50%

•ST-segment deviation on ECG presentation

•At least 2 anginal events in prior 24 hours

•Use of aspirin in prior 7 days

•Elevated serum cardiac biomarkers

8

Variables Used in the TIMI Risk Score

The TIMI risk score is determined by the sum of the presence of the above 7 variables at admission. 1 point is given for each variable. Primary coronary stenosis of 50% or more remained relatively insensitive to missing information and remained a significant predictor of events.

TIMI Risk

Score

All-Cause Mortality, New or Recurrent MI, or Severe Recurrent Ischemia Requiring Urgent

Revascularization Through 14 Days After Randomization %

0-1 4.7

2 8.3

3 13.2

4 19.9

5 26.2

6-7 40.9

9

TIMI Risk Score

Early Hospital care

Anti ischemic therapy and analgesic therapy

– Bed rest with continuous ECG monitoring– Supplemental oxygen ( if spo2<90% or respiratory

distress).– sublingual nitrate every 5 min for a total of 3 doses .– IV NTG in first 48 hrs

- persistent ischemia

- HF

- hypertension

class 1

Anti ischemic therapy contd..

- Oral beta-blocker therapy ( within the 1st 24 h)

Contraindications: 1) signs of HF

2) low out put state( SBP<90,oliguria,HR<50)

3) other relative contraindications to beta blockade.

(PR > 0.24 s, 2nd or 3rd degree AV block,

active asthma or reactive airway disease).

4) increased risk for cardiogenic shock

class 1

Risk factors for increased cardiogenic shock

• Older age• Female sex• Time delay• Higher killip class• SBP<120• HR>110 or <60

If Beta blockers are contra indicated

Nondihdropyridine calcium channel blockers

- Verapamil

- Diltiazem

Contraindications for CCBs:

Severe LV dysfunction

15

COMMIT Trial

•45,852 patients within 24 h acute MI― 93% STEMI or LBBB, 7% had NSTEMI

•Up to 15 mg IV → 50 mg po metoprolol daily v/s placebo

• composite primary outcomes ― death, reinfarction, or cardiac arrest

•No decrease of com-primary outcome by metoprolol - modest reduction in reinfarctions and VF

• Risk cardiogenic shock especially with initial hemodynamic instability•Recommend: start -blocker po when hemodynamically stable

ACEI & ARBs

ACE inhibitor (orally within 1st 24 h) in patients with

- pulmonary congestion

- LVEF ≤ 40%

contraindications:

- hypotension

(SBP < 100 mm Hg or < 30mm Hg below baseline)

- known contraindications ACEIs

ARBs: if intolerance to ACEI

(class IIa)

IV morphine

IV beta blocker : in HTN with UA/NSTEMI

( with no CI for Beta Blocker)

Oral long acting non-DHP CCBs :

for recurrent ischemia if no CI

( after nitrates and beta blockers) Oral ACEI

- in pts with out - pulmonary congestion

- LVEF≤ 40%

Intra aortic balloon counter pulsations (IABP)

• For continuing severe ischemia• For hemodynamic unstability

Class IIa

Nitrates :

- SBP<90 or ≥ 30mm Hg below the baseline.

- with in 24 hr of PDEIs ( sildenafil& tadalafil)

IV ACEI : ↑ ed risk of hypotension

IV beta blockers : with CI to Beta blockade

NSAIDs ( except ASA):

a/w ↑ mortality, reinfarction, HTN, HF,

myocardial rupture

Class III

Antiplatelet therapy

Antiplatelet therapy

Aspirin : as soon as possible (165-325 mg)

- (non enteric formulation orally or chewed).

-Continued indefinitely(75-162mg/d ) in pts who

tolerate it.

Clopidogrel :

- loading dose -300mg

- daily maintenance dose 75mg

- Continued for at least 1 month and ideally up to 1 year.

class 1

CURE trial

• 12,562 patients with UA/NSTEMI presenting with in 24 hrs• Clopidogrel 300mg loading >>>75mg/d v/s placebo• All patients received ASA

• Significant reductions in the rate of in-hospital severe ischemia and revascularization and need for IV GPIIb/IIIa inhibitors.

• Strong evidence for addition of clopidogrel to ASA on admission in management of patients in whom a non-interventional approach is intended.

• Useful approach in hospitals that do not have a routine policy about early invasive procedures

Use of Proton pump inhibitors

Interfere with the metabolism of clopidogrel

-

- Lansoprazole inhibits CYP450 2C19

- Rabeprazole

Omeprazole : significantly decrease the inhibitory effect of

clopidogrel on platelet aggregation.

Pantoprazole lacks inhibition of CYP450 2C19

Omeprazole

-- Deleted recommendation 2011

Anti coagulant therapy recommendationsClass I

Invasive strategy: - UFH - Enoxaparin - Bivalirudin

Conservative strategy: - UFH or Enoxaparin

- Fondaparinux

( preferable in pts with increased risk of bleeding)

Enoxaparin or fondaparinux preferable to UFH unless CABG is planned with in 24 hrs Class IIa

UFH dosage

• ACC/AHA Guidelines recommend

weight-adjusted dose of UFH

: 60 units/kg bolus and

: 12 units/kg/hr infusion.

Select Management Strategy:

Initial Conservative Strategy Versus

Initial Invasive strategy

UA/NSTEMI

ASA( Clopidogrel if

ASA intolerance)Conservative strategy Invasive strategy

Anticoagulant therapy:Enoxaparin or UFH

Fondaparinux

Anticoagulant therapy:Enoxaparin or UFH

Bivalirudin

Pre cath:Add second antiplatelet agent:-Clopidogrel-GPIIb/IIIA inhibtor(IV eptifibatide or tirofiban)

Initiate clopidogrel

Next step per triage decision at angiography

CABG:Maintenance ASA

PCI:Clopidogrel (if not begun precath)OrPrasugrel OrGPIIB/IIIA inhibitor (if not begun precath

Medical therapy:-D/C GPIIb/IIIainhibitor and give clopidogrel as per conservative strategy

Initial Conservative management Strategy

ASA+

Anticoagulant therapy

-ASA continued indefinitely-Clpidogrel continued for at least 1 month and ideally up to 1 year

Conservative strategyUA/NSTEMI

Enoxaparin, UFH, Bivalirudin, Fondaparinux

Clpidogrel (30-600 mg→→ 75mg)

UA/NSTEMI- conservative strategy

No subsequent features that necessitates CAG

Stress testing

High Risk Low risk

CAG

-ASA indefinitely-Clopidogrel – 1 month (ideally up to 1 year)-Discontinue IV GPIIb/IIIa inhibitor if started previously-Continue UFH for 48 hrs or administer enoxaparin or fondaparinux max up to 8days or duration of hospitalization

Class 1

LV EFEF<40% EF>40%

ACC/AHA noninvasive risk stratfication: high risk (>3% annual mortality rate)

• severe resting LV dysfunction (LVEF<35%)• High risk TMT score (score≤ -11)• Severe exercise LV dysfunction (LVEF<35%)• Stress induced large perfusion defect (if ant.)• Stress induced multiple perfusion defects• Large fixed perfusion defect with LV dialatation or increased

lung uptake (thallium 201)• Stress induced moderate perfusion defect with LV dialatation

or increased lung uptake (thallium 201)• Echo wall motion abn.at low dose dobutamine • Stress echo evidence of extensive ischemia

Class IIaUA/NSTEMI- Conservative Strategy

Recurrent ischemic discomfort with ASA+ Clopidogrel+Anticoagulant treatment

Add a GPIIb/IIIa inhibitor before diagnostic CAG

Omit GPIIB/IIIa inhibitors if bivalirudin is selected as the anticoagulant & 300-600 mg clopidogrel was administered 6 hours earlier than

planned CAG or PCI

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•Cont ASA .

•DC clopidogrel 5 to 7 d prior to elective CABG.

• DC IV GP IIb/IIIa 4 h prior to CABG

•Cont UFH • 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

• Cont ASA

• LD of clopidogrel if not given pre angio

&• IV GP IIb/IIIa if not started

pre angio

• DC ACT after PCI for uncomplicated cases

• Cont ASA

• LD of clopidogrel if not given pre angio

• DC IV GP IIb/IIIa after at least 12 h if started pre angio

• Cont IV UFH for at least 48 h or enoxaparin or fondaparinux for dur of hosp ;

• either DC bivalirudin or cont at a dose of 0.25 mg/kg/hr for up to 72 h at physician‘s discretion .

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

UA/NSTEMI- CABG selected as post angiography management

--Continue ASA -Discontinue clopidogrel - 5 days prior to CABG-(discontinue prasugrel - 7 days prior to CABG)

-Discontinue IV GPIIb/IIIa inhibitor (eptifibatide or tirofiban) 4 hrs before CABG.

-Continue UFH- Discontinue enoxaparin & fondaparinux 12-24 hrs bfore CABG and dose with UFH per institutional practice-Discontinue bivalirudin 3 hours before CABG and dose with UFH as per institutional practice

Class 1

UA/NSTEMI- PCI has been selected as post angiography management

-

Class 1A

-Continue ASA - loading dose of thienopyridines if not given before CAG – - clopidogrel 300-600 mg - prasugrel 60 mg

-IV GPIIa/IIIa inhibitor (abciximab, eptifibatide, tirofiban ) if not started before CAG (in troponin-positive and /or high risk patients)

-Discontinue anticoagulant therapy after PCI for uncomplicated cases

- Class IIa

UA/NSTEMI –medical therapy is selected as management strategy

+ obstructive CAD

-ASA-clopidogrel-discontinue IV GPIIb/IIIa inhibitor if started previously

Anti coagulant therapy

Continue intravenous UFH for at least 48 h or until discharge if given before diagnostic angiographyContinue enoxaparin or fondaparinux for duration of hospitalization or up to 8 days.Discontinue Bivalirudin

UA/NSTEMI –medical therapy is selected as management strategy

-No significant obstructive CAD-

Antiplatelet and anticoagulant therapy at the discretion of physician

Luminal irregularities with out flow limiting lesions –long term ASA

UA/NSTEMI – conservative strategy-who do not undergo CAG or stress testing

-ASA indefinitely-Clopidogrel for at least 1 month ( ideally up to 1 year)-Discontinue GPIIb/IIIa inhibitor if started previously

-Continue UFH for 48 hrs or-Enoxaparin or fondaparinux ( 8 days or dur.hosp.)

Initial Invasive management strategy

41Bavry AA, et al. J Am Coll Cardiol 2006;48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk.

Relative Risk of All-Cause Mortality for Early Invasive Therapy Compared With Conservative Therapy at a Mean Follow-Up of 2 y

42Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. CI = confidence interval; RR = relative risk. Reprinted with permission from Elsevier.

Relative Risk of Recurrent Nonfatal MI for Early Invasive Therapy Compared With Conservative Therapy at a

Mean Follow-Up of 2 y

43

Relative Risk of Recurrent UA Resulting in Rehospitalisation for Early Invasive Therapy Compared With Conservative

Therapy at a Mean Follow-Up of 13 Months

Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk; UA = unstable angina.

- refractory angina

- hemodynamic instability

- arrhythmias

- Elevated risk of clinical events

Recommendations for initial invasive strategies

Class I

Initially stabilized high risk patients –reasonable to choose early invasive strategy

(With in 12-12 hrs) Class IIa

High risk clinical events

Recurrent angina/ischemia at rest with low-level activities despite intensive medical therapy

Elevated cardiac TnT or TnI

New/presumably new ST- segment depression

Signs/symptoms of heart failure or new/worsening mitral regurgitation

High-risk findings from noninvasive testing

Hemodynamic instability

Sustained ventricular tachycardia

PCI within 6 months

Prior CABG

High risk score (e.g., TIMI, GRACE)

- LVEF < 40%)

Dual –antiplatelet on presentation

Before PCI-clopidogrel orIV GpIIb/IIIainhibitor-tirofiban or eptifibatideAt the time of PCI-clopidogrel (if not started) or PrasugrelIV GpIIb/IIIa-tirofiban or eptifibatide (if not begun pre catheterization)

Invasive strategyUA/NSTEMI

Initiate anticoagulant therapy :

Enoxaparin or UFHBivalirudin

Recommendations in whom PCI is planned (2011)

Clopidogrel loading 300-600 mg should be given as early as possible before or at the time of PCI

OrPrasugrel 60 mg should be given promptly and not later than 1 hour after PCI once coronary artery anatomy is defined.

Class 1

Class III

No Abciximab to patients in whom PCI is not planned. Upstream GPIIa/IIIa inhibitors are not recommended in -TIMI score ≤ 2( low risk for ischemic events) - at high risk of bleeding

Prasugrel contraindicated in -Prior h/o TIA or stroke

Duration and maintenance of thienopyridine therapy (2011)

Clopidogrel 75 mg daily or Prasugrel 10 mg daily

Duration : Up to 12 months

If the risk of morbidity because of bleeding outweighs the benefit by thienopyridine therapy earlier discontinuation can be considered

Class 1

Medical therapy BMS group DES group

ASA 75-162 mg/d indefinitely

&Clopidogrel 75

mg/d for at least 1 month and

ideally up to 1 year

ASA 162-325 mg/d (1 month)

↓75-162 mg/d (indefinitely)

&Clopidogrel 75

mg/d or Prasugrel 10 mg/d (for at least 1 year)

ASA 162-325 mg/d (SES-3months)(PES-6months)

↓75-162 mg/d (indefinitely)

&Clopidogrel 75 mg/d

Or prasugrel 10mg for

at least 1 year

Long term Antiplatelet therapy

Class I

2011 new recommendation

• Continuation of clopidogrel /prasugrel beyond 15 months may be considered in patients following DES placement

class IIb

52

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

Lipid Management

Lipid management should include assessment of a fasting lipid profile for all patients, within 24 h of hospitalization.

High dose statins in the absence of contraindications, regardless of baseline LDL-C and diet modification, should be given to post-UA/NSTEMI patients, including post revascularization patients.

LDL goal: <100mg/dl

<70 mg/dl reasonable (classIIa)

Meta analysis of intensive v/s standard statin therapy, showing a highly significant 16% reduction in the risk of coronary death or

MI (p<0.0001)

Lipid Management contd..

Dietary therapy :-Reduced intake of saturated fats to < 7% of total calories-cholesterol to < 200 mg per d - trans fat (to < 1% of energy).

Promoting daily physical activity and weight management are recommended

Lipid Management

If TG are ≥ 500 mg per dL: - Fibrate or niacin

LDL-C be treated to goal after TG-lowering therapy.

High dose statin+ fibrate can increase the risk of severe myopathy

Statin doses kept low in this combination

Blood Pressure Control

Blood pressure control according to JNC 7 guidelines is recommended

(i.e., BP < 140/90 mm Hg or < 130/80 mm Hg if the patient has diabetes mellitus or chronic kidney disease).

Diabetes mellitus

• Use insulin infusion to control hypeglycemia• control blood glucose from a more stringent to

a more moderate target range .• Recommend treatment for hyperglycemia>180

mg/dl while avoiding hypogylcemia

• NICE-SUGAR trial:

ADA RECOMMENDATION

“ Although hyperglycemia is associated with adverse outcomes after acute MI, reduction of glycemia per se and necessarily the use of insulin is a/w improved outcomes”

Chronic Kidney Disease

Creatinine clearance should be estimated in UA/NSTEMI patients.Doses of renally cleared drugs should be adjusted according to the pharmacokinetic data of specific medications.

Chronic Kidney Disease contd…

Patients undergoing CAG with receipt of contrast mediashould receive adequate preparatory hydration.

Calculation of the contrast volume to Cr Cl ratio is useful to predict the maximum volume of contrast media that can be given with out significantly increasing the risk of contrast associated nephropathy

TIME IS PRECIOUS

• Creatinine clearance( an approximation of GFR)

• is measured from plasma and urinary creatinine excretion rates for a defined time period (usually 24 h)

• is expressed in milliliters per minute:• CrCl = (Uvol x UCr)/(PCr x Tmin).

• Cockcroft-Gault: • CrCl (mL/min) = (140 – age (years) x weight

(kg) x [0.85 if female])/(72 x sCr (mg/dL)

76

Fragmin during Instability in Coronary Artery Disease (FRISC-2)

• Patients within 48 h UA/NSTEMI

• Early inv vs conserv & dalteparin vs placebo

• 3048 patients → dalteparin for 5–7 d → 2457 continued dalteparin/placebo & received either inv or conserv rx strategy

• Meds: ASA, β-blockers unless contraindicated

• No ↓ death/MI @ 3 mo by dalteparin

• ↓ Death/MI @ 6 mo, 1 y & 5 y for inv strategy

― Benefit confined to men, nonsmokers, and patients with ≥ 2 risk factors

Wallentin L, et al. Lancet 2000;356:9–16 (1-year results). Lagerqvist B, et al. J Am Coll Cardiol 2001;38:41–8 (women vs men). Lagerqvist B, et al. Lancet 2006;368:998–1004 (5-yr follow-up).

77

Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy

(TACTICS-TIMI-18)

• 2,220 patients within 24 h UA/NSTEMI• Early inv or conserv (selective invasive) strategy• Meds: ASA, heparin and tirofiban• ↓ Death, MI, and rehosp for an ACS @ 6 mo for inv strategy

― Benefit in medium and high-risk patients (TnT ↑ of > 0.01 ng/mL, ST-segment deviation, TIMI risk score > 3)― No high-risk features, outcomes ↔― ↓ Death/MI @ 6 mo for older adults with early inv strategy― Benefit of early inv strategy for high-risk women (↑ TnT); low-risk women tended to have worse outcomes, incl ↑ risk of major bleeding

Cannon CP, et al. N Engl J Med 2001;344:1879–87.

78

Third RandomizedIntervention Treatment of Angina (RITA-3)

• 1,810 moderate-risk ACS patients

• Early inv or conserv (ischemia-driven) strategy

• Exclusions: CK-MB > 2X ULN @ randomization, new Q-waves, MI w/in 1 mo, PCI w/in 1 y, any prior CABG

• ↓ Death, MI, & refractory angina for inv strategy

― Benefit driven primarily by ↓ in refractory angina

• ↓ Death/MI @ 5 y for early inv arm

• No benefit of early inv strategy in women

Fox KA, et al. Lancet 2002;360:743–51. Fox KA, et al. Lancet 2005;366:914–20 (5-y results).

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Clopidogrel in Unstable angina to preventRecurrent ischemic Events (CURE)

•12,562 patients within 24 h UA/NSTEMI

•Placebo vs clopidogrel (LD 300 mg → 75 mg qd)

•Other meds: ASA

•↓ CV death, MI, or stroke, rate of recurrent ischemia & revasc with clopidogrel

•↑ Major (non–life-threatening) bleeding with clopidogrel

•No routine inv strategy, 23% revasc during initial admission

•Although well tolerated, < 10% GP IIb/IIIa + ASA + clopidogrel + heparin use in study patients

Yusuf S, et al. N Engl J Med 2001;345:494–502.

80

Platelet Receptor Inhibition in Ischemic Syndrome Managementin Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS)

•1,915 patients within 12 h UA/NSTEMI

•Tirofiban alone, UFH alone, or both for 48–108 h.

•Tirofiban-alone arm discontinued d/t ↑ mortality rate.

•↓ Death, MI, or refractory ischemia at 7 d, 30 d & 6 mo by tirofiban + heparin

•High rate of angio could have contributed to important ↓ in event rates

•Recommend: Tirofiban + heparin for medical rx or during PCI

PRISM-PLUS Study Investigators. N Engl J Med 1998;338:1488–97.

82Bavry AA, et al. J Am Coll Cardiol 2006;48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk.

Relative Risk of All-Cause Mortality for Early Invasive Therapy Compared With Conservative

Therapy at a Mean Follow-Up of 2 y

83Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. CI = confidence interval; RR = relative risk. Reprinted with permission from Elsevier.

Relative Risk of Recurrent Nonfatal MI for Early Invasive Therapy Compared With Conservative Therapy at a

Mean Follow-Up of 2 y

84

Relative Risk of Recurrent UA Resulting in Rehospitalisation for Early Invasive Therapy Compared With Conservative

Therapy at a Mean Follow-Up of 13 Months

Bavry AA, et al. J Am Coll Cardiol 2006; 48:1319–1325. Reprinted with permission from Elsevier. CI = confidence interval; RR = relative risk; UA = unstable angina.

85

SYMPTOMS SUGGESTIVE OF ACS

Noncardiac Diagnosis

Chronic Stable Angina

Possible ACS

Definite ACS

Treatment as indicated by

alternative diagnosis

ACC/AHA Chronic Stable Angina

Guidelines

No ST-Elevation ST-Elevation

Nondiagnostic ECG Normal initial serum cardiac biomarkers

ST and/or T wave changes

Ongoing pain

Positive cardiac biomarkers

Hemodynamic abnormalities

Evaluate for reperfusion

therapy

ACC/AHA STEMI Guidelines

Observe

≥ 12 h from symptom onset

No recurrent pain; negative follow-up studies

Recurrent ischemic pain or positive follow-up studies

Diagnosis of ACS confirmed

Stress study to provoke ischemia

Consider evaluation of LV function if ischemia is present (tests may be

performed either prior to discharge or as outpatient)

Negative

Potential diagnoses: nonischemic discomfort; low-

risk ACS

Arrangements for outpatient follow-up

Positive

Diagnosis of ACS confirmed or highly likely

Admit to hospital

Manage via acute ischemia pathway