Adjunctive Therapy to PCI

with UA/NSTEMI

Sendhil Krishnan
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%
 Sites of Antithrombotic Drug Action
Coagulation cascade Platelet cascade
Intrinsic Pathway Platelet Activation

Plasma clotting
Agonist Activation of
cascade
degranulation GP IIb-IIIa

LMWHProthrombin Clopid Other

agonists

Factor
ogrel ADP TxA2
A
Xa
S
UFH AT III* Platelet recruitment and A
aggregation
Thrombin
Bivalir
Fibrinogen cross links to form
udin platelet-rich thrombus
GP IIb-IIIa
inhibitors
Thrombo
Formation of
lytics Fibrin Mesh mature thrombus
*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.
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
TIMI IIIB UA or NSTEMI <24 hrs of rest
angina treated with heparin/ASA
Early Invasive(18- Conservative*
48 hrs) n=740 n=733
Death 2.4 2.5
Nonfatal MI 5.1 5.7
+ 6 wk ETT 8.6 10
Total 16.2 18.1 P=.33
Hospital days 10.2 10.9
Rehospitalization 7.8 14.1
within 6 wks
*High rate of cross-over to invasive group, 58 % at 1 yr
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 did
worse: Received thrombolysis, no ST segment
depression, w/out hx of MI
• Large percentage of cross-over, 33%
FRISC II

• 2457 pts with unstable coronary

disease, randomly assigned after 48
hrs to invasive or conservative
approach
• Intervention within 7 days
• LMWH Heparin/ASA/ +/-Dalteparin
 FRISC II Invasive Non-invasive Risk
(1222 pts) (1235 pts) Ratio

Death, MI,or 113 (9.4%) 148 (12.1%) .78

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

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

(p=.1)
Angina, 6 256 (22%) 455 (39%) .56
months
Readmission, 6 357 (31%) 594 (49%) .62
months
 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, 15.9 19.4
Rehosp for
ACS*
Death or 7.3 9.5
nonfatal MI*
*6 months
 VBWG

Median time to angiography 22 hrs

Median time to revasc 25 (PCI) to 89 (CABG) hrs
RITA 3

• 1810 pts with NSTEMI randomized within 48 hrs

of 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 MI
reduced (9.4 vs 14.1)
 VBWG

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
 Optimal Strategy for UA/NSTEMI
ISAR-COOL

RITA-3
VANQWISH VINO
MATE
TRUCS

TIMI IIIB TACTICS-

TIMI 18

FRISC II
Invasive
Conservative Invasive
Patients (N): 920 1674 7018

Adapted with permission from Cannon CP, Turpie AG. Circulation. 2003;107:2640-2645.
15
 VBWG

Summary

• Benefit in all but VANQWISH and TIMI-IIIB in the

early invasive group
• Advancements in anticoagulation and stents
could 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

Invasive Strategy Preferred:

• An early invasive strategy is indicated in initially
stabilized patients who have an elevated risk for
clinical events (I, A). Scores indicating elevated risk
include 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
Initial Invasive Strategy
• Initiate anticoagulant therapy as soon as
possible 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)
– Clopidogrel
– IV GP IIb/IIIa inhibitor
Use both if:
• Delay to angiography
• High risk features
• Early recurrent ischemic symptoms
 VBWG

• UFH vs. LMWH?

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.)
CURE: Clopidogrel in Unstable Angina
to prevent Recurrent ischemic Events
• 12,562 patients with non-ST elevation acute coronary
syndrome 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.
VBWG
PCI-CURE Study: Benefit of Clopidogrel
Pretreatment With PCI and Stenting
Composite of MI, Urgent Revascularization,
or CV Death at 30 Days
.08
Cumulative Hazard Rate

Placebo + Aspirin
.06 Pretreated* 44%
Relative
Risk
.04 Reduction

.02 Clopidogrel + Aspirin

P=.016
Pretreated*
(0.35-0.90)
.00
0 5 10 15 20 25 30
Days of Follow-up

*In addition to other standard therapies.

Patients did not receive open-label thienopyridine before PCI.
26
Mehta SR, et al. Lancet. 2001;358:527-533. © 2001 by The Lancet Ltd.
PCI-CURE Study: CV Death or MI
From Randomization
.15 Placebo + Aspirin*
Median 12.6%
time to PCI
(n=1345) 31%
Cumulative Hazard Rate

Relative
Risk
.10 Reduction
8.8%

Clopidogrel + Aspirin*
.05 (n=1313)

P=.002
.00
0 10 100 200 300 400
Days of Follow-up
*In combination with standard therapy.
27
Mehta SR, et al. Lancet. 2001;358:527-533. © 2001 by The Lancet Ltd.
VBWG
VBWG
VBWG
VBWG
VBWG
VBWG
 VBWG
Mortality risk is lower with early
(<24-hour) GP IIb/IIIa inhibition

Favors Favors Adjusted OR (95% Cl)

early GP IIb/IIIa no early GP IIb/IIIa
inhibitor inhibitor
6 RCTs ACS 0.91 (0.81–1.02)
(N = 31,402)
CRUSADE ACS
0.93 (0.83–1.05)
(N = 49,378)
CRUSADE Tn+
0.88 (0.77–1.01)
(n = 32,290)

NRMI NSTEMI
0.88 (0.79–0.97)
(n = 60,770)

0.5 1.0 2.0

Odds ratio
RCT = randomized control trial Boersma E et al. Lancet. 2002;359:189-98.
Tn+ = troponin positive Hoekstra JW et al. Acad Emerg Med. 2005;12:431-8.
 VBWG
ACC/AHA guidelines for UA/NSTEMI:
GP IIb/IIIa inhibitors

I IIa IIb III

A platelet GP IIb/IIIa antagonist should be administered in
addition to ASA and heparin to patients in whom cardiac
catheterization and PCI are planned. GP IIb/IIIa antagonists may
also be administered just prior to PCI.

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.

• Direct Thrombin Inhibitors

– Don’t require antithrombin and can inhibit clot-bound thrombin, don’t

interact with plasma proteins, don’t cause thrombocytopenia

– The only current U.S. FDA–approved indication for lepirudin and

argatroban 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 of

three 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 patients

receiving supplemental GP IIb/IIIa inhibitors did not change efficacy
or safety outcomes, but the strategy of bivalirudin alone was
associated with less bleeding than the combination of a GP IIb/IIIa
inhibitor with either UFH or enoxaparin.
 VBWG
ACC/AHA UA/NSTEMI Guidelines:
Management of high-risk patients

High-risk patients
• Signs of ischemia at rest >20 minutes AND ST-segment
depression and/or elevated cardiac biomarkers

Immediate treatment (Class Ia)

• ASA or clopidogrel if ASA contraindicated
• LMWH or UFH
• GP IIb/IIIa inhibitor

Diagnostic catheterization and revascularization

within 24–48 hours (Class Ia)

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

 VBWG

Recommended therapies for UA/NSTEMI

Acute therapies (<24h) Discharge therapies

• Aspirin • Aspirin
∀ β-Blocker • Clopidogrel
• Heparin (UFH or LMWH) ∀ β-Blocker
• GP IIb/IIIa inhibitor • ACE inhibitor
(all receiving PCI/cath)
• Statin/lipid lowering
• Clopidogrel (all receiving PCI)
• Smoking cessation
• Catheterization/
• Cardiac rehabilitation
revascularization ≤48 hours

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

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 <0.40
despite conventional therapy including ACE or ARB (IIb, B)
• Angiotensin Receptor Blocker (ARB) should be administered
at discharge (I, A) and long-term (IIa, B) with ACE inhibitor
intolerance and signs of HF with LVEF < 0.40 (I, A).
Discharge Planning: Secondary Prevention (2)

• Aldosterone receptor blockade should be prescribed

long term if without significant renal dysfunction or
hyperkalemia, 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 <100 mg/dl (I, A), with <70 mg/dl reasonable (IIa, A)
– Treatment of triglycerides and non-HDL-C useful
• If TG 200-499 mg/dl, non-HDL-C should be <130 mg/dl (I, B)
• TG ≥500 mg/dl, fibrate or niacin before LDL-C lowering to prevent
pancreatitis (I, C)
Discharge Planning: Secondary Prevention (3)

• Blood Pressure Control

– <140/90 mmHg (I, A)
– <130/80 mmHg with diabetes mellitus or chronic
kidney disease (I, A)

• Smoking cessation and avoidance of

exposure to environmental tobacco is
recommended (I, B)
– Education, referral to programs and
pharmacotherapy is useful (I, B)