adjunctive rx nstemi

8/14/2019 Adjunctive Rx Nstemi

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Adjunctive Therapy to PCI

with UA/NSTEMI

Sendhil Krishnan


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AMI

GUSTO IIb trial performed in the early 1990s

Mortality 30 day 6 months 1 year

STEMI 6% 8% 9.6%

NSTEMI 5.7% 8.8% 11.1%

UA 2.4% 5% 7%


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Thrombin

Fibrin Mesh

Fibrinogen cross links to formplatelet-rich thrombus

Activation ofGP IIb-IIIa

TxA2ADP

AT III*

FactorXa

LMWH

Thrombolytics

ASA

Clopidogrel

Platelet Activation

Agonist

degranulation

Prothrombin

Platelet recruitment and aggregation

Formation of

mature thrombus

Plasma clottingcascade

Intrinsic Pathway

Bivalir

udin

UFH

*AT III = antithrombin III.

Stein B, et al. J Am Coll Cardiol. 1989;14(4):813-836; DeJong MJ, et al. Crit Care Nurs Clin N Am. 1999;11(3):355-371; White HD.Am J Cardiol. 1997;80(4A):2B-10B.

Sites of Antithrombotic Drug ActionCoagulation cascade Platelet cascade

GP IIb-IIIainhibitors

Other

agonists


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Clinical Trials: Case For PCI Strategy

TIMI IIIB, 1995

VANQUISH, 1998

MATE, 1998 FRISC II, 1999

TACTICS-TIMI 18, 2001

RITA 3, 2002

VINO, 2002

ISAR-COOL, 2003


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TIMI IIIB UA or NSTEMI


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VANQWISH

920 pts with NSTEMI, 97% men Early invasive w/in 72 hrs of last chest pain vs

conservative

ASA, Heparin

No benefit in invasive group (only 44% of pts)

At discharge: Death or Nonfatal MI 7.8 vs 3.2,

Trend present at 1 yr and not at 2 yr

Subset analysis of invasive population which didworse: Received thrombolysis, no ST segmentdepression, w/out hx of MI

Large percentage of cross-over, 33%


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FRISC II

2457 pts with unstable coronary

disease, randomly assigned after 48

hrs to invasive or conservativeapproach

Intervention within 7 days LMWH Heparin/ASA/ +/-Dalteparin


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FRISC II Invasive

(1222 pts)

Non-invasive

(1235 pts)

Risk

Ratio

Death, MI,or

both

113 (9.4%) 148 (12.1%) .78

MI 94 (7.8%) 124(10.1%) .77

Death 23 (1.9%) 36(2.9%) .65

(p=.1)

Angina, 6

months

256 (22%) 455 (39%) .56

Readmission, 6

months

357 (31%) 594 (49%) .62


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TACTICS-TIMI 18

2220 pts UA/NSTEMI undergoing invasive(4-48 hrs) or conservative approach

ASA, IV heparin, tirofiban

Benefit only noted if positive Troponin

Invasive Conservative

Death, MI,

Rehosp forACS*

15.9 19.4

Death or

nonfatal MI*

7.3 9.5

*6 months


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VBWG

Median time to angiography 22 hrsMedian time to revasc 25 PCI to 89 CABG hrs


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RITA 3

1810 pts with NSTEMI randomized within 48 hrsof initial chest pain

Enoxaparin, ASA 4 months- Improved combined end pt of death,

nonfatal MI, or refractory angina (9.6 vs 14.5)Results due to angina reduction

1 year- Death+nonfatal MI (7.6 vs 8.3) and MIreduced (9.4 vs 14.1)


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VINO

131 pts with NSTEMI within 24 hrs of last chest

pain

ASA/ IV heparin/ Ticlopidine if stented

Six month improvement in mortality (3.1 vs

13.4%) death or reinfarction (6 vs 22% in

conservative) Despite 40% of conservative pts undergoing

catheterization by then

VBWG


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15

Patients (N): 920 1674 7018

Adapted with permission from Cannon CP, Turpie AG. Circulation. 2003;107:2640-2645.

Optimal Strategy for UA/NSTEMI

Conservative Invasive

TIMI IIIB

MATE

VANQWISH

InvasiveFRISC II

TACTICS-TIMI 18

VINO

RITA-3

TRUCS

ISAR-COOL


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Summary

Benefit in all but VANQWISH and TIMI-IIIB in the

early invasive group

Advancements in anticoagulation and stentscould have some role

Most benefit in moderate to high risk groups

Elevated Troponin: FRISC II & TACTICS-TIMI 18 ST depression on the ECG in >1 lead: FRISC II,

TACTICS-TIMI 18, and TIMI IIIB Age> 65: TIMI IIIB

VBWG


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Invasive Strategy Preferred:

An early invasive strategy is indicated in initiallystabilized patients who have an elevated risk forclinical events (I, A). Scores indicating elevated riskinclude combinations of the following: Recurrent angina/ischemia at rest or low-level activities Elevated cardiac biomarkers New/presumably new ST-segment depression Signs or symptoms of HF 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 LVEF < 0.40

VBWG


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Initial Invasive Strategy

Initiate anticoagulant therapy as soon aspossible after presentation (I, A)

Enoxaparin or UFH (I, A)Bivalirudin or fondaparinux (I, B)

Prior to angiography, initiate one (I, A) or both(IIa, B)

ClopidogrelIV GP IIb/IIIa inhibitorUse both if:

Delay to angiography High risk features Early recurrent ischemic symptoms


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UFH vs. LMWH?

VBWG


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2007 UA/NSTEMI Guideline Update

Anticoagulant therapy:

a) In patients treated with conservative therapy, the

preferred anticoagulant may be fondaparinux,

enoxaparin (for 8 days or duration of hospitalization),

or unfractionated heparin (UFH) (for 48 hours) (in that

order).

b) In patients treated with invasive therapy,

enoxaparin or UFH-based regimens have the most

supporting evidence.

Fondaparinux assoc. w/ 3x increased risk of catheter-

related thrombi (also observed with STEMI pts.)


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CURE: Clopidogrel in Unstable Angina

to prevent Recurrent ischemic Events

12,562 patients with non-ST elevation acute coronarysyndrome with either positive biomarkers myocardial

injury or new ECG changes.

These patients were randomized to receive either an

immediate loading dose of 300 mg of clopidogrel,administered in the emergency room as soon as the

diagnosis was made, followed by 75 mg/day for up to

one year, or they were randomized to matching placebo.


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VBWG


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26*In addition to other standard therapies.

Patients did not receive open-label thienopyridine before PCI.

Mehta SR, et al. Lancet. 2001;358:527-533. 2001 by The Lancet Ltd.

Composite of MI, Urgent Revascularization,or CV Death at 30 Days

Days of Follow-up

44%

RelativeRiskReduction

0 5 10 15 20 25 30.00

.02

.04

.06

.08

CumulativeHazardRate

P=.016

(0.35-0.90)

Clopidogrel + Aspirin

Pretreated*

Placebo + Aspirin

Pretreated*

PCI-CURE Study: Benefit of Clopidogrel

Pretreatment With PCI and Stenting


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27*In combination with standard therapy.Mehta SR, et al. Lancet. 2001;358:527-533. 2001 by The Lancet Ltd.

.00

.05

.10

.15

0 10 100 300 400200

CumulativeHa

zardRate

Clopidogrel + Aspirin*

(n=1313)

31%Relative

Risk

Reduction

Placebo + Aspirin*(n=1345)Median

time to PCI

Days of Follow-up

12.6%

8.8%

P=.002

PCI-CURE Study: CV Death or MIFrom Randomization


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VBWG


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VBWG


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VBWG

Boersma E et al. Lancet. 2002;359:189-98.

Hoekstra JW et al.Acad Emerg Med. 2005;12:431-8.

RCT = randomized control trial

Tn+ = troponin positive

0.88 (0.790.97)

NRMI NSTEMI

(n = 60,770)

Adjusted OR (95% Cl)Favors

early GP IIb/IIIa

inhibitor

Favors

no early GP IIb/IIIa

inhibitor

0.93 (0.831.05)CRUSADE ACS

(N = 49,378)

0.88 (0.771.01)CRUSADE Tn+

(n = 32,290)

0.5 1.0 2.0

Odds ratio

6 RCTs ACS

(N = 31,402)0.91 (0.811.02)

Mortality risk is lower with early

(


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VBWG

A platelet GP IIb/IIIa antagonist should be administered in

addition to ASA and heparin to patients in whomcardiac

catheterization and PCI are planned. GP IIb/IIIa antagonists may

also be administered just prior to PCI.

II IIaIIa IIbIIb IIIIII

Eptifibatide or tirofiban should be administered in addition to ASA

and heparin in patients with continuing ischemia, elevated

troponin, or other high-risk features in whom an invasive

management strategy is not planned.

A platelet GP IIb/IIIa antagonist should be administered to

patients already receiving heparin, ASA, and clopidogrel in whom

cardiac catheterization and PCI are planned. GP IIb/IIIa

antagonists may also be administered just prior to PCI.

Braunwald E et al. J Am Coll Cardiol. 2002;40:1366-74.

ACC/AHA guidelines for UA/NSTEMI:

GP IIb/IIIa inhibitors


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Direct Thrombin Inhibitors

Dont require antithrombin and can inhibit clot-bound thrombin, dontinteract with plasma proteins, dont cause thrombocytopenia

The only current U.S. FDAapproved indication for lepirudin andargatroban is for anticoagulation in patients with heparin-induced

thrombocytopenia (HIT) and associated thromboembolic disease.

ACUITY trial randomized 13,819 patients with UA/NSTEMI to one ofthree treatments: UFH or enoxaparin plus a GP IIb/IIIa inhibitor,bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone

Substitution of bivalirudin as the anticoagulant among patientsreceiving supplemental GP IIb/IIIa inhibitors did not change efficacyor safety outcomes, but the strategy of bivalirudin alone wasassociated with less bleeding than the combination of a GP IIb/IIIainhibitor with either UFH or enoxaparin.


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VBWG


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VBWG

High-risk patients

Signs of ischemia at rest >20 minutes AND ST-segment

depression and/or elevated cardiac biomarkers

Diagnostic catheterization and revascularization

within 2448 hours (Class Ia)

Braunwald E et al. J Am Coll Cardiol. 2002;40;1366-74.

ACC/AHA UA/NSTEMI Guidelines:

Management of high-risk patients

Immediate treatment (Class Ia)

ASA or clopidogrel if ASA contraindicated

LMWH or UFH

GP IIb/IIIa inhibitor

VBWG


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VBWG

Braunwald E et al. J Am Coll Cardiol. 2002;40:1355-74.

Recommended therapies for UA/NSTEMI

Aspirin

-Blocker Heparin (UFH or LMWH)

GP IIb/IIIa inhibitor

(all receiving PCI/cath)

Clopidogrel (all receiving PCI)

Catheterization/

revascularization 48 hours

Aspirin

Clopidogrel

-Blocker ACE inhibitor

Statin/lipid lowering

Smoking cessation

Cardiac rehabilitation

Acute therapies (


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Discharge Planning: Secondary Prevention (1)

Clopidogrel, initial conservative strategy Continue at least 1 mo (I, A) Continue ideally up to 1 yr (I, A)

ACE inhibitor

Continue indefinitely with HF, LV dysfunction with LVEF < 0.40,hypertension or diabetes (I, A) Reasonable in absence of LV dysfunction, hypertension or diabetes

(IIa, A) Reasonable with HF and LVEF >0.40 (IIa, A) Consider ACE/ARB combination with persistent HF and LVEF


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Aldosterone receptor blockade should be prescribedlong term if without significant renal dysfunction orhyperkalemia, already on ACE inhibitor, with LVEF< 0.40, and either symptomatic HF or diabetes (I, A).

Lipid management Statin regardless of baseline LDL-C (I, A) initiated prior to discharge (I,

A) Goal LDL-C


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Blood Pressure Control

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