Mx of UA and NSTEMIAlyssa Morris, R4September 30, 2010

OBJECTIVES

Mx of UA/NSTEMI in the ED CRUSADE, COMMIT, ISIS-2, CAPRIE, CURE,

PCI-CURE, OASIS-5, OASIS- 7, SYNERGYNOT covering

GPIIb/IIIa inhibitors Statins Decision to go to PCI or medical

management Variants of ACS

LEVEL OF EVIDENCE

See handout

TERMINOLOGY

Stable Angina Angina brought on by exertion and

relieved with predictable measures (rest/NTG)

Unstable Angina/ACS New onset angina w/i 2/12 and at least

CCS III Rest angina lasting >20min w/i 1wk of

angina Change from baseline

NSTEMI/ACS + markers

TERMINOLOGY Acute Coronary Syndromes is the

preferred terminology to refer a spectrum of disease related to myocardial ischemia

(stable angina)

Unstable Angina

NSTEMI

STEMI

+/- abN ECG, -ve markers

+/- abN ECG, +ve markers

STE on ECG, +ve markers

CASE

60M with RSCP with a +TNT at 6 hrs after pain started, no STE on multiple ECGs

BP= 176/98, P= 90, 02= 94%How would you treat this

person? Write down all that you would do What do you think the NNT for each of

your therapies is?

TREATMENT STRATEGIES

ANTI-ISCHEMIC Inc supply: nitrates, oxygen Dec demand: BB, morphine, ACE-I

ANTI-PLATELET ASA, Clopidogrel, GPIIb/IIIa inhibitors

ANTI-THROMBOTIC Medical: UFH, LMWH, thrombolytics Invasive: PCI/CABG

ANTI-INFLAMMATORY Statins

ANTI-ISCHEMIC TREATMENT

OXYGEN- AHA guidelines

LOE: B Administered to UA/NSTEMI pts with:

Sa02<90% Respiratory distress Other high-risk features for hypoxemia

LOE: C Reasonable to administer to all

patients in 1st 6hrs from presentation

NITRATES

Reduces myocardial oxygen demand while enhancing myocardial oxygen delivery

Venous dilation Arterial dilation

Peripheral and coronary arteries

NITRATES- AHA guidelines LOE: C Sublingual NTG for ongoing ischemic

discomfort 0.4mg Q5min, max of 3 doses

Assess need for IV NTG Persistent pain, HF, HTN Q: How do you titrate your nitro drip?

Not if SBP<90, HR<50, PDE I in last 24-48hr

MORPHINE- AHA guidelines Venodilation Modest reductions in HR (inc vagal

tone)Modest reductions in SBP

CLASS IIa/ LOE B Reasonable to administer it IV if

uncontrolled ischemic chest pain despite NTG

Provided you use additional therapy to manage the ischemia

Nonrandomized, retrospective, observational study

N= 57,039 (w NSTEMI) 17,003 (29.8%) received morphine

Higher adjusted risk of death (OR 1.48, 95% CI 1.33-1.64

BETA BLOCKERS

Competitively block the effects of catecholamines on cell membrane R Reduce myocardial contractility Reduce sinus node rate Reduces AV node conduction

velocity

Randomized trial N= 45,852

93% had STE or LBBB 7% had NSTEMI

Randomized to metoprolol or placebo IV max 15mg then 200mg PO OD

No reduction in composite of death, reinfarction or cardiac arrest Less VFIB later in study

Increased risk of cardiogenic shock in 1st day

BETA BLOCKERS- AHA guidelinesCLASS I/ LOE B

Oral BB should be started w/i 24hr in patients who do not have 1 of:1) Signs of HF, 2) low-output state, 3)

increased risk for cardiogenic shock, 4) other contraindications to BB

CLASS II/ LOE B Reasonable to administer IV BB at time

of presentation for HTN who do not have 1 of above

CCBs

Reduce cell transmembrane inward Ca flux Inhibits myocardial and vascular smooth

muscle contraction Some also slow AV conduction and

depress sinus node impulse formation Verapamil and diltiazem

Coronary dilation Benefit is from reduced myocardial

oxygen demand and improved myocardial flow

CCBs- AHA guidelines

CLASS I/ LOE B Nondihydropyridine CCBs should be given

to pts with ongoing or frequently occurring ischemic pain in whom BB are contraindicated

Not if LV dysfunction or other CIsCLASS IIb/ LOE B

Can use ER nondihydropyridine CCB instead of a BB

Can only use IR dihydropyridine in adequately BB pt

ACE-I – AHA guidelines

CLASS I/ LOE A Should be started orally w/i 24h in pts

with pulmonary congestion or LVEF <0.4 in absence of hypotension (SBP<100)

CLASS IIa/ LOE B Can be used in patients w/o pulmonary

congestion or LVEF <0.4CLASS III

IV should not be given in the 1st 24h b/c of increased risk of hypotension

NSAIDS- AHA guidelines

CLASS I/LOE C b/c of increased risk of mortality,

reinfarction, htn, HF and myocardial rupture associated with their use, NSAIDs (except ASA) should be discontinued and not administered

ANTIPLATELET TREATMENT

ASA

Irreversibly inhibits COX-1 w/i platelets Diminishes platelet aggregation Fully present even with low dose

ASA

Meta-analyses of RCTs 195 trials, 143,000 patients22% reduction in the odds of

vascular death, MI, or strokeARR 6.1%, NNT 1675mg to 1500mg of ASA showed

similar reductions in the odds of vascular events

RCT N= 17,187 pts with suspected acute

MI Randomized to 1month of ASA

26 fewer deaths per 1000 during first 35d

ARR for 35d mortality 2.4% RRR for 35d mortality 23% NNT=43 (to prevent one death) Showed benefit if given early

ASA- AHA guidelines

CLASS I/ LOE A ASA should be administered asap and

continued indefinitely In pts with hx of GIB a PPI should be

used CIs

Intolerance and allergy Active bleeding Hemophilia Severe untreated htn

PLAVIX

Platelet effects are irreversible but take several days to achieve Loading dose shortens this time

substantiallyDifferent mechanism than ASA

Potential exists for for additive benefit

Adenosine diphosphate receptor antagonist

Randomised, blinded international study

Efficacy of ASA and Clopidogrel (75mg OD) in reducing risk of a composite of ischemic stroke, MI, vascular death

N= 19,185, Included recent ischemic stroke, MI or symptomatic peripheral artery dz

Plavix annual risk of 5.32% vs ASA 5.83% (P=0.043) (NNT= 194)

No difference in AE

RCT N= 12,562 with UA/NSTEMI Placebo or Clopidogrel (300mg loading

dose then 75mg daily) All pts received ASA Outcome: 1) composite of death from CV

cause, MI or stroke 2) refractory ischemia Results: 1) placebo 11.4% vs Clopidogrel

9.3% 2) placebo 18.8% vs clopidogrel 16.5% (p<0.001) (20% RRR, 2.1% ARR, NNT= 48)

Observational substudy of CURE N= 2658 pts undergoing PCI Received the loading dose of Plavix

then daily for 10 days, then they got thienopyridine for 4 weeks, then plavix restarted

Outcome: composite of death, MI or urgent revascularization

Results: placebo 6.4% vs clopidogrel 4.5% (p=0.03) (ARR= 3.8%, NNT= 26)

RCT 45852 pts, 7% had UA/NSTEMI Plavix 75mg OD or placebo Outcomes: 1) composite of death,

reinfarction or stroke; 2) death from any cause

ARR 0.9% and NNT 111 Concluded that adding plavix to ASA

safely reduces mortality and major vascular evens and should be done routinely

Plavix- How much?

Approved loading dose in UA/NSTEMI is 300mg

600mg does achieve antiplatelet fxn more quickly Not enough good evidence to use this much

Considerable inter-individual variation in antiplatelet effect with all loading doses

O mg if you believe pt going to CABG Increased risk of minor bleeding Some believe benefit outweighs risk

RCT2x2 factorial design N= 25,086 w ACS, >70% had UA/NSTEMI Invasive strategy + loading dose of 600mg

Plavix or 300mg Plavix High or low dose ASA also given randomly Outcome: cardiovascular death, myocardial

infarction or stroke at 30d 4.2% in high Plavix vs 4.4% standard Plavix Secondary outcome of stent thrombosis in

those with PCI (HD 1.6% v SD 2.3%, p= 0.001)

PLAVIX – AHA guidelines

CLASS I Plavix should be given to pts who are

unable to take ASA (LOE A) Pts with hx GIB should get a PPI if getting

Plavix (LOE B) Plavix should be given to pts in addition

to ASA in pts who are receiving an initial invasive stratgey (LOE B)

Plavix should be given to pts in addition to ASA in pts who are receiving conservative therapy (LOE B)

ANTICOAGULANT TREATMENT

UFH

UFH Accelerates action of antithrombin

inactivates factor IIa (thrombin), factor IXa and Xa

Prevents thrombus propagation but does not lyse existing thrombi

Binds to a number of plasma proteins, blood cells and endothelial cells

LMWH

LMWH From depolymerization of chains of

heparin Inactivate Xa>IIa (b/c of molecular weight) Advantages:▪ decreased binding to plasma proteins and

endothelial cells ▪ Dose-independent clearance ▪ Longer half-life that results in more

predictable and sustained anticoagulation w SC administration

Synthetic Factor Xa Inhibitors Fondaparinux

Synthetic pentasaccharide Acts proximally in cascade to inhibit

multiplier effects of the downstream coagulation rxns reduce amount of thrombi that is generated

Indirect, selective factor Xa inhibitor Binds to antithrombin III Same advantages as LMWH

Fondaparinux: pharmacology

Pharmacologic comparisonPharmacotherapy 23(6):772-787, 2003Property UFH LMWH FondaparinuxSource animal animal synthetic

T1/2 ~3h ~4h (variable) 17-21hBioavailability

(SC) 30% >90% 100%

Elimination Reticuloendothelial and renal renal renal

Induced HIT* 2-5% 1-2% Not observedInter or intra-

patient variability

+++ ++ +

Monitoring aPTTPlt count Plt count nil

Reversal Protamine Protamine FFP

Prospective, randomized, open-label N= 10027 high-risk UA/NSTEMI pts w early

invasive strategy Compare enoxaparin to UFH for composite

endpoint of all-cause death or MI in 30d 14% in enox group vs 14.5% in UFH group

(p=0.4) More bleeding in enox group

Post-hoc showed from switching type of anticoagulant at time of PCI

Low molecular weight heparins vs unfrctionated heparin for acute coronary syndromesMagee KD, Sevcik W, Moher D, Rowe BH

To assess the effects of LMWH compared to UFH for ACS (UA/NSTEMI)

7 studies involving over 10,000 people No difference in overall mortality LMWH showed reduced recurrence of MI

and the need for revascularization procedures

No difference in recurrent angina, major bleeds, or minor bleeds; there was a decrease in the incidence of HIT

125 patients have to be treated with LMWH to prevent 1 MI, and 50 have to be treated to prevent 1 revascularization procedure

Cochrane Database of Systematic Reviews 2003

N=

RCDBT, industry sponsored, non-inferiority

N= 20,078, UA/NSTEMI patients Enox 1mg SC BID v Fonda 2.5mg SC

OD + UFH at PCI if last dose >6hr ago

Outcomes: 1) death, MI or refractory ischemia at 9d; 2) major bleeding

1) 5.8% w fonda v 5.7% w enox Satisfies non-inferiority criteria

2) 2.2% w fonda v 4.1% w enox (p<0.001)

ANTICOAGULANT Mx- AHA guidelines CLASS I

Should be added to antiplt therapy at presentation Invasive Strategy LOE A▪ UFH or Enoxaparin

Invasive Strategy LOE B ▪ Fondaparinux

Conservative strategy LOE A▪ UFH or enoxaparin

Conservative strategy LOE B▪ Fondaparinux

Use fondaparinux if increased risk of bleeding

SUMMARY

BB ASA

NNT 16 in meta-analysis NNT 43 in ISIS-2

Plavix NNT 48 in CURE NNT 194 in CAPRIE NNT 26 in PCI-CURE NNT 111 in COMMIT

Anticoagulant