Transcript Review of Evidence Antithrombotics in Non ST Elevation ACS

Dr.Tahsin.N
3 - 2 - 2012

ANTIPLATELETS
ASPIRIN
Antiplatelet Trialists’ Collaboration

Meta-analysis of randomized trials of antiplatelet therapy for
prevention of death, MI, and stroke in high-risk patients

195 trials and > 143,000 pts

22% ↓ in odds of vascular death, MI, or stroke with antiplatelet
therapy
across broad spectrum of clinical presentations that included
UA/NSTEMI

Similar ↓ in odds of vascular events with aspirin doses of 75-1500 mg
daily; <75 mg benefit ↓; dose-dependent ↑ bleeding
Meta-analysis Comparing Use of Long-term ASA vs.
Control
Secondary prevention trials (pts at high average risk):
― Serious vascular events – RR: 0.81; p<0.0001
― CHD Death – RR: 0.87; p=0.02
― Any stroke – RR: 0.81; p=0.002
― Bleeds – RR: 2.69; p=0.01
CLOPIDOGREL
Clopidogrel in Unstable angina to prevent
Recurrent ischemic Events (CURE)

12,562 patients within 24 h UA/NSTEMI

Placebo vs clopidogrel (LD 300 mg → 75 mg qd)

Other meds: aspirin

↓ CV death, MI, or stroke, rate of recurrent ischemia & revasc with
clopidogrel


↑ Major (non–life-threatening) bleeding with clopidogrel
23% revasc during initial admission
Antiplatelet therapy for
Reduction of MYocardial Damage during Angioplasty
(ARMYDA-2)
Patients with stable angina or UA/NSTEMI
Clopidogrel 600 mg LD (n=126) vs clopidogrel 300 mg LD
(n=129) 4 to 8 h
before PCI
↓ Death, MI or TVR up to 30 days by 600 mg LD
― Benefit d/t ↓ periprocedural MI
Small study of relatively low-risk patients, low use of GP IIb/IIIa
CURRENT-OASIS 7
25,086 pts with ACS, intended PCI,
Clopidogrel
Double-dose (600 mg d1, 150 mg d2 to 7, then 75 mg daily) vs. standarddose (300 mg d1, then 75 mg daily)
Aspirin
High-dose (300 to 325 mg daily) vs. low-dose (75 to 100 mg daily)
Primary outcome: CV death, MI, or stroke at 30 days – No significant difference
in overall trial
― ↑ major bleeding with double-dose clopidogrel vs. standard dose
(2.5% vs. 2.0%, HR: 1.24; p=0.012)
Primary outcome: CV death, MI, or stroke at 30 days (PCI subgroup)
― ↓ double-dose clopidogrel vs. standard dose, 3.9% vs. 4.5%,
p=0.035
― High-dose and low-dose aspirin did not differ
Definite stent thrombosis ↓ with double-dose vs standard dose clopidogrel, 0.7%
vs. 1.3%, Adj HR: 0.54; p=0.0001 (PCI subgroup)
Tailored Clopidogrel LD According to Platelet Reactivity
Monitoring

Investigated ↓ stent thrombosis with tailored clopidogrel LD

429 PCI pts with low clopidogrel response after 600 mg LD

VASP guided pts (up to 3 additional clopidogrel 600 mg LDs) → VASP
index <50% (vasodilator-stimulated phosphoprotein flow cytometry
assays)

Stent thrombosis at 1 m significantly ↓ in VASP group vs. control (0.5%
vs. 4.2%; p<0.01)

MACE higher in control group (8.9% vs. 0.5%; p<0.001)

No difference in bleeding rate (2.8% vs 3.7%; p=0.8)

Tailored clopidogrel LD according to platelet reactivity monitoring ↓ early
stent thrombosis after PCI without ↑ bleeding
Point-of-care Assay: Residual Platelet Reactivity (RPR) to ADP
for ACS Patients on DAPT Undergoing PCI/stent
RPR measured with VerifyNow P2Y12 assay: clopidogrel non-responsiveness
Single 600 mg clopidogrel LD followed by 75 mg of clopidogrel daily (100 to
325 mg ASA daily)
12 m follow-up: 51 ischemic events
RPR values ≥240 were significant / independent predictor of:
― CV death (HR: 2.55; p=0.034)
― Nonfatal MI (HR: 3.36; p=0.004)
― No significant association high RPR and TVR
RPR to ADP point-of-care assay can detect ACS pts at ↑ risk of CV death and
nonfatal MI at 12 m (optimal cutoff value 240 P2Y12 reaction units)
Meta-analysis: Clopidogrel Non-responsiveness and CV
Mortality Post PCI
14 studies, 4,564 CAD pts
Residual platelet reactivity (despite clopidogrel treatment) significantly
associated with ↑ risk of death and/or thrombotic recurrence (OR: 5.67;
p<0.00001)
Significant association between residual platelet reactivity and recurrent CV
events (clopidogrel non – responsiveness)
PRASUGREL,CANGRELOR,TICAGRELOR
TRITON-TIMI 38
Moderate / high-risk ACS pts (n=13,608) scheduled for PCI randomized to:
― Prasugrel (60 mg LD and 10 mg daily MD) or
― Clopidogrel (300 mg LD and 75 mg daily MD) for 6 to 15 months
Primary end point (CV death, nonfatal MI, nonfatal stroke), 9.9% prasugrel vs
12.1% clopidogrel (HR: 0.81; p<0.001)
Prasugrel significant ↓ MI (7.4% vs. 9.7%; p<0.001), urgent TVR (2.5% vs.
3.7%), stent thrombosis (1.1% vs. 2.4%)
Prasugrel significantly ↓ ischemic events, including stent thrombosis but ↑ risk
major bleeding, including fatal bleeding
Overall mortality did not differ significantly between groups
TRITON-TIMI 38
Trial Design: TRITON-TIMI 38 was a randomized, double-blind trial of prasugrel (n = 6,813)
compared to clopidogrel (n = 6,795) in patients undergoing planned PCI for an acute coronary
syndrome (ACS). Primary endpoint was CV death, MI or stroke with a median follow-up of 14.5
months.
Death, MI, or
stroke
HR 0.81
p < 0.001
15
Major
Bleeding
4
HR 1.32
p = 0.03
12.1
3
2.4
%
10
9.9
2
1.8
5
1
0
0
Prasugrel
Clopidogrel
Results
• CV death, MI or stroke ↓ with prasugrel vs
clopidogrel (Figure)
• Stent thrombosis also ↓ with prasugrel (1.1% vs.
2.4%, HR 0.48, p < 0.001)
• TIMI major non-CABG bleeding ↑ with prasugrel
than clopidogrel (Figure),
• Net clinical benefit endpoint (primary+bleeding)
favored prasugrel (12.2% vs. 13.9%, HR 0.87, p =
0.004)
Conclusions
• Among patients undergoing planned PCI for ACS,
treatment with novel thienopyridine, prasugrel, was
associated with reduction in composite of CV death,
MI or stroke compared with clopidogrel
• As would be expected with greater platelet
inhibition, bleeding events were significantly higher
in prasugrel group, including life-threatening and
fatal bleeding
• Despite this increase, net clinical benefit endpoint
incorporating mortality, ischemic events, and major
bleeding events, favored prasugrel
PLATO
Trial design: Patients with ACS were randomized to ticagrelor (180 mg loading dose, 90
mg bid thereafter) or clopidogrel (300 mg loading dose, 75 mg daily thereafter). Patients
were followed for 12 months.
Results
30
(p < 0.001)
10
5.9
10
9.8
11.7
%5
Death from vascular cause, MI, stroke lower
in ticagrelor arm, including in patients
undergoing PCI
•
Mortality, stent thrombosis (p = 0.02) ↓
with ticagrelor; stroke rate similar (p = 0.22)
•
No increase in fatal bleeding or overall
major bleeding, but higher rate of nonCABG major bleeding (p = 0.03)
(p < 0.001)
20
%
•
4.5
Conclusions
0
0
Primary endpoint
Ticagrelor
(n = 9,333)
All-cause mortality
Clopidogrel
(n = 9,291)
• Ticagrelor superior to clopidogrel for several
outcomes including death, MI, and stent
thrombosis in patients presenting with ACS
• Very promising results; reduction in CV mortality
notable in the modern era of ACS
Cannon CP, et al. Lancet 2010;375:283-93
PLATO
PLATO
INNOVATE PCI
Trial design: Patients undergoing nonurgent PCI were randomized to one of four groups prior to
PCI: 1) elinogrel 80 mg IV, then 150 mg oral twice daily (n = 207); 2) elinogrel 80 mg IV, then 100 mg
oral twice daily (n = 201); 3) elinogrel 80 mg IV, then 50 mg oral twice daily; or 4) clopidogrel 300600 mg, then 75 mg daily (n = 208).
Results
•
•
(p = NS)
6
•
%
4.0
2.8
3
•
No TIMI major bleeds in any group
Numerical increase in access bleeds requiring
medical attention with higher doses of
elinogrel compared with clopidogrel
Death, MI, stroke, or revascularization:
approximately 2.8% of the elinogrel 150 mg
group, 4% of the elinogrel 100 mg group, and
1.5% of the clopidogrel group (p = NS)
Dyspnea: 12.1%, 15.4%, and 4.3%
1.5
Conclusions
0
• Among patients undergoing nonurgent PCI, the use
of elinogrel is feasible
ischemic
Death, MI, stroke,
or revascularization
Elinogrel
150 mg
Elinogrel
100 mg
Clopidogrel
• Access site bleeds were numerically higher with
increasing doses of elinogrel
• Similar to ticagrelor, dyspnea was more common
with study drug
Presented by Dr. Sunil Raul at ESC 2010
ACCEL-RESISTANCE
Trial design: Patients undergoing PCI, and with high platelet reactivity 12 hours after
loading dose of 300 mg clopidogrel were randomized to receive cilostazol with clopidogrel
75 mg daily or clopidogrel 150 mg daily. Patients were followed for 30 days.
(p < 0.001)
(p = 0.015)
Results
•
Cilostazol was associated with a significant
↓ in MPA with 5 and 20 μmol/L ADP
compared with high-dose clopidogrel
100
100
•
Cilostazol was associated with a higher %
platelet inhibition (48.4% vs. 35.7%)
80
80
•
Clinical endpoints were not measured
60
% 40
57.2
60
42.1
%
40
20
0
MPA reduction with
20 μmol/L ADP
Cilostazol + clopidogrel
(n = 30)
48.4
35.7
Conclusions
• Cilostazol was associated with greater reduction in
platelet activity compared with high-dose
clopidogrel in patients with high platelet reactivity
20
0
% platelet inhibition
High-dose clopidogrel
(n = 30)
• Clinical endpoints were not available; long-term
outcomes need to be assessed as well
Jeong YH, et al. J Am Coll Cardiol 2009;53:1101-9
GP IIb / IIIa INHIBITORS
Intracoronary Stenting and Antithrombotic Regimen–
Rapid Early Action for Coronary Treatment (ISAR-REACT)-2
2,022 patients within 48 h high-risk UA/NSTEMI
aspirin + clopidogrel + abciximab vs aspirin + clopidogrel + placebo
600 mg LD clopidogrel ≥2 h before PCI → abciximab or placebo
↓ Death, MI, or urgent TVR by 30 d with abciximab
- ↓ If cTnT +
- no diff if cTnT –
No diff major/minor bleeding
Recommend: GP IIb/IIIa + clopidogrel if inv strategy used and high risk acs
(Class IIa, LOE: B)
ACUITY Timing Trial
Routine upstream Gp IIb/IIIa inhibitors vs. deferred selective Gp IIb/IIIa use in
pts with moderate and high-risk ACS undergoing early, invasive treatment.
Composite ischemia at 30 days: 7.1% in upstream vs. 7.9% in deferred (RR:
1.12; p=0.044 for noninferiority; p=0.13 for superiority)
30-day rates of major bleeding: 6.1% in upstream vs. 4.9% in deferred (p<0.001
for noninferiority; p=0.009 for superiority)
Net clinical outcomes similar: 11.7% in upstream vs. 11.7% in deferred
(p<0.001 for noninferiority; p≤0.93 for superiority)
Deferred routine upstream Gp IIb/IIIa inhibitors for selective administration in
cath lab only to patients undergoing PCI resulted in ↑ composite ischemia
(while not statistically significant), BUT Decreased bleeding risk
Platelet Receptor Inhibition in Ischemic Syndrome
Management (PRISM)
3,232 patients within 24 h UA/NSTEMI
Tirofiban vs UFH over 48 h
Other meds: aspirin
↓ Death, MI, or refractory ischemia at 48 h & 7 d by tirofiban
― ↓ Death/MI @ 30 d
― No ↑ bleeding; thrombocytopenia ↑
Platelet Receptor Inhibition in Ischemic Syndrome
Management in Patients Limited by Unstable Signs and
Symptoms (PRISM-PLUS)
1,915 patients within 12 h UA/NSTEMI – higher risk
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
Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor
Suppression Using InTegrilin (PURSUIT)
10,948 patients within 24 h UA/NSTEMI
Low-dose eptifibatide (n=1,487) vs high-dose eptifibatide (n=4,722) vs placebo
(n=4,739)
Other meds: aspirin, heparin
↓ Death/MI @ 96 hours, 7 d, 30 d with eptifibatide
― 1.5% ARR 4–30 d
― ↑ major bleeding
― no diff stroke
↑ Event rate in 11% of patients not treated with concomitant heparin
Early versus Delayed Provisional Eptifibatide
in Acute Myocardial Infarction EARLY ACS
9492 patients with NSTEMI ACS
Early routine vs. delayed, provisional eptifibatide
Primary end point: death, MI, recurrent ischemia requiring urgent
revascularization, or thrombotic complication during PCI that required
bolus therapy
― 9.3% early eptifibatide vs. 10.0% delayed eptifibatide
EARLY ACS
Secondary end point: death or MI within first 30 d
― 11.2% early eptifibatide vs. 12.3% delayed eptifibatide
Eptifibatide 12 h or more before angiography not superior to provisional use
after angiography
― associated  risk non-life-threatening bleeding, need for transfusion
Thank you
……to be continued
MCQs
Match the trial with drug
1.
ISAR REACT 2
a) CLOPIDOGREL
2.
ISAR CHOICE
b) PRASUGREL
3.
JUMBO TIMI 26
c) TICAGRELOR
4.
PLATO
d) ELINOGREL
5.
INNOVATE PCI
e) ABSCIXIMAB
6.
PRISM
f) EPTIFIBATIDE
7.
PURSUIT
g) TIROFIBAN
8. Vascular death, MI, or stroke are decreased with antiplatelet therapy by
a) 18%
b) 22%
c) 26%
d) 30%
9. All the following trials compared 600mg clopidogrel with 300mg except
a)
CURE
b) ISAR CHOICE
c)
ARMYDA 2
d) CURRENT OASIS 7
10. Regarding TRITON TIMI38 all the following statements are true EXCEPT
a)
Prasugrel significant ↓ MI & urgent TVR
b) Prasugrel significantly ↓ ischemic events, including stent thrombosis
c)
Prasugrel ↑ risk of major bleeding, including fatal bleeding
d) Prasugrel reduced overall mortality
11. Regarding PLATO trial all are true EXCEPT
Ticagrelor compared to clopidogrel
a.
Decreased mortality
b.
Increased overall bleeding
c.
Caused significant dyspnoae
d.
Reversible
12. Regarding Pursuit trial All are true EXCEPT
Eptifibatide Caused
a)
1.5% Absolute reduction
b) ↑ major bleeding
c)
Increased stroke
d) One of the largest GP IIb / IIIa trial
ANSWERS
Match the trial with drug
1.
ISAR REACT 2
a) CLOPIDOGREL
2.
ISAR CHOICE
b) PRASUGREL
3.
JUMBO TIMI 26
c) TICAGRELOR
4.
PLATO
d) ELINOGREL
5.
INNOVATE PCI
e) ABSCIXIMAB
6.
PRISM
f) EPTIFIBATIDE
7.
PURSUIT
g) TIROFIBAN
8. Vascular death, MI, or stroke are decreased with antiplatelet therapy by
a) 18%
b) 22%
c) 26%
d) 30%
9. All the following trials compared 600mg clopidogrel with 300mg except
a)
CURE
b) ISAR CHOICE
c)
ARMYDA 2
d) CURRENT OASIS 7
10. Regarding TRITON TIMI38 all the following statements are true EXCEPT
a)
Prasugrel significant ↓ MI & urgent TVR
b) Prasugrel significantly ↓ ischemic events, including stent thrombosis
c)
Prasugrel ↑ risk of major bleeding, including fatal bleeding
d) Prasugrel reduced overall mortality
11. Regarding PLATO trial all are true EXCEPT
Ticagrelor compared to clopidogrel
a.
Decreased mortality
b.
Increased overall bleeding
c.
Caused significant dyspnoae
d.
Reversible
12. Regarding PURSUIT trial All are true EXCEPT
Eptifibatide Caused
a)
1.5% Absolute reduction
b) ↑ major bleeding
c)
Increased stroke
d) One of the largest GP IIb / IIIa trial
Dr.Tahsin.N
10 - 2 - 2012
Anticoagulants
HEPARIN & LMWH
Efficacy and Safety of Subcutaneous Enoxaparin in
Non-Q-Wave Coronary Events (ESSENCE) trial
3,171 patients within 24 h UA/NSTEMI
Enoxaparin vs UFH
Other meds: aspirin
↓ Death, MI or recurrent angina for enox @ 14 d, 30d and 1 y
― minor bleeding ↑
― major bleeding ↔
Thrombolysis In Myocardial Ischemia trial, phase 11B (TIMI
11B)
3,910 patients within 24 h UA/NSTEMI
Enoxaparin vs UFH
Other meds: aspirin
↓ Death, MI or urgent revasc for enox @ 48 h, 8 d, 14 d, & 43 d
↑ major & minor bleeding (inhosp) with enox
Superior Yield of the New strategy of Enoxaparin,
Revascularization and Gp IIb/IIIa Inhibitors (SYNERGY)
•9,978 patients within 24 h high-risk UA/NSTEMI
•Enoxaparin vs UFH → early inv strategy
•Other meds: aspirin, clopidogrel, GP IIb/IIIa @ physician discretion
•Enox noninferior for death/MI @ 30 d, 6 mo 1 y
•↑ Major bleeding with enox
― ? due to crossover to UFH @ time of PCI
SYNERGY Primary Outcomes
1.0
14.5
14
14
12
10
UFH
Enoxaparin
8
6
Freedom from Death/MI
16
0.95
0.9
0.85
Enoxaparin
UFH
4
0.8
0
2
5
10
15
20
25
30
Days from Randomization
0
Death or MI
at 30 d
Absolute Risk Reduction
Hazard Ratio
95% CI
p
Kaplan Meier Curve
0.5
0.96
0.86–1.06
0.40
Reprinted with permission from Ferguson JJ, et al. JAMA 2004;292:45–54.
Antithrombotic Combination Using Tirofiban and Enoxaparin
(ACUTE II)
525 patients within 24 h UA/NSTEMI
Enoxaparin vs UFH
Other meds: aspirin, tirofiban LD 0.4 mcg/kg over 30 min → 0.1
mcg/kg/min
No ↓ death/MI during first 30 d
― Trend to lower event rates with enox
No ↓ major/minor bleeding
Aggrastat to Zocor (A to Z)
3,987 patients within 24 h UA/NSTEMI on aspirin & tirofiban
Enoxaparin vs UFH
Coronary angio in 60% of pts
No ↓ all-cause mortality, MI or refractory ischemia w/in 7 d by enox
― Nonsig trend to ↓ ischemic events with enox
↑ Major bleeding with enox
INTegrilin and Enoxaparin Randomized Assessment of Acute
Coronary syndrome Treatment (INTERACT)
746 patients within 24 h high-risk UA/NSTEMI
Enoxaparin vs UFH
Other meds: aspirin, eptifibatide 180 mcg/kg IV bolus → 2.0 mcg/kg/min
infusion for 48 hours
↓ Death/MI for enox @ 30 d
Minor bleeding - ↑ for enox @ 96 h, no diff by 30 d
Major bleeding - ↓ for enox @ 96 h (1o safety endpoint)
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: aspirin, β-blockers unless contraindicated
No ↓ death/MI @ 3 mo by dalteparin
↓ Death/MI @ 6 mo, 1 y & 5 y for inv strategy
Meta analysis Enoxaparin Vs UFH - DEATH
Meta analysis Enoxaparin Vs UFH - MI
Meta analysis Enoxaparin Vs UFH – Major bleed
FONDAPARINUX
Organization to
Assess Strategies for Ischaemic Syndromes (OASIS-5)
Fondaparinux (2.5 mg/day, n=10,057) vs enoxaparin (1.0 mg/kg BID, n=10,021) in
UA/NSTEMI patients
― Enox patients undergoing PCI → UFH if last dose of enox > 6 h before PCI
Other meds: aspirin, clopidogrel, GP IIb/IIIa @ investigator discretion
No ↓ death, MI or refractory ischemia @ 9 d by fonda
― Non inferiority criteria met
↓ Major bleeding with fonda
↓ Death @ 30 d and 180 d and ↓ death, MI and stroke @ 180 d with fonda
↑ Catheter-assoc thrombus with fonda
OASIS 5 Cumulative Risk of Death, MI, or Refractory
Ischemia
10
9.0
9
8
7.3
7
5.7
6
Enoxaparin
5.8
Fondaparinux
5
4.1
4
3
2.2
2
1
0
OASIS 5 Death, MI, or refractory
ischemia at 9 days
Absolute Risk Reduction
Hazard Ratio
Confidence Interval
p
-0.1
1.01
0.90–1.13
0.007*
OASIS 5 Major bleeding at 9
days
1.9
0.52
0.44–0.61
< 0.001†
*p for noninferiority; †p for superiority. Yusuf S, et al. N Engl J Med 2006;354:1464–76.
OASIS 5 Composite primary
outcome and major bleeding at 9 days
1.7
0.81
0.73–0.89
< 0.001†
FUTURA/OASIS-8
Trial design: NSTEMI patients initially treated with fondaparinux 2.5 mg SQ were randomized to
unfractionated heparin 50 U/kg regardless of glycoprotein IIb/IIIa inhibitor use (n = 1,024) vs.
unfractionated heparin 60 U/kg with glycoprotein IIb/IIIa inhibitor or 85 U/kg without glycoprotein
IIb/IIIa inhibitor (n = 1,002).
(p = 0.27)
Results
•
5.8
6
%
(p = 0.06)
4.7
•
4.5
•
2.9
3
Major bleeds/minor bleeds/vascular access
site complications at 48 hours: 4.7% of the
low-dose heparin group vs. 5.8% of the
standard-dose heparin group (p = 0.27)
Death, MI, or revascularization: 4.5% vs. 2.9%
(p = 0.06), respectively
Stent thrombosis: 1.2% vs. 0.5% (p = 0.11),
respectively
Conclusions
0
bleeding bleed,
Major/minor
or vascular
complication
Low-dose
heparin
outcome
Death,
MI, or
revascularization
Standard-dose
heparin
• Among ACS patients initially treated with
fondaparinux, PCI can be safely performed with the
addition of unfractionated heparin
• Low-dose and standard-dose heparin had the same
frequency of bleeding events
• Low-dose heparin therapy was associated with a
marginally significant increase in ischemic events
FUTURA/OASIS-8 Trial Group. JAMA
2010;Aug 31:[Epub]
BIVALIRUDIN
Acute Catheterization and Urgent Intervention
Triage strategY (ACUITY)
Within 24 h UA/NSTEMI → heparin (enox/UFH) ± upstream GP IIb/IIIa
(n=4603) vs bivalirudin (bival) ± upstream GP IIb/IIIa (n=4604) vs bival alone +
provisional GP IIb/IIIa (n=4612)
Compared to heparin + GP IIb/IIa:
― Bival + GP IIb/IIIa noninferior for composite ischemia, major
bleeding & net clinical outcomes @ 30 d
― Bival alone noninferior for composite ischemia; ↓ major bleeding;
↓ net clinical outcomes @ 30 d
ACUITY Clinical Outcomes at 30 d
14
11.7
12
11.8
10
8
7.3
7.7
UFH or Enoxaparin + GP IIb/IIIa
5.7
6
5.3
Bivalirudin + GP IIb/IIIa
4
2
0
ACUITY Composite ACUITY Major bleeding at
ischemia endpoint at 30
30 days
days
Absolute Risk Reduction
Hazard Ratio
95% CI
p
-0.4
1.07
0.92–1.23
0.007*
0.4
0.93
0.78–1.10
< 0.001*
ACUITY Net clinical
outcome at 30 days
-0.1
1.01
0.90–1.12
< 0.001*
ACUITY Composite Ischemia & Bleeding
Outcomes
10
9.1
9
7.8
8
7.3
7
7.3
7.0
7.1
UFH + GP IIb/IIIa
5.7
6
Bivalirudin alone
5
4
3.0
3
2
1
0
Ischemia endpoint by
ACUITY Major bleeding at 30
ACUITY Composite ischemia Ischemia endpoint by
endpoint at 30 days
thienopyridine loading thienopyridine loading before
days
angiography or PCI No
before angiography or
PCI YES
Absolute Risk Reduction
Hazard Ratio
95% CI
p
-0.5
1.08
0.93–1.24
0.32
0.3
-2.0
0.97
1.29
0.80–1.17
1.03–1.63
0.054 (for interaction)
2.7
0.53
0.43–0.65
< 0.001
ISAR-REACT 3
Trial design: Troponin-negative patients undergoing PCI were randomized to either
bivalirudin or unfractionated heparin (UFH), after pretreatment with 600 mg of clopidogrel.
Clinical outcomes were evaluated at 30 days.
Results
(p = 0.57)
10
9
8
7
6
%5
4
3
2
1
0
8.3 8.7
(p = 0.008)
5
3.1 4.6
• Bleeding significantly ↓ with bivalirudin
compared with UFH: major (33%), minor (31%)
4
3
%
2
Conclusions
• Bivalirudin is not superior to UFH as adjunct
anticoagulation therapy for troponin-negative
patients undergoing PCI, who were pretreated
with 600 mg of clopidogrel
1
0
Composite endpoint
Bivalirudin
(n = 2,289)
• Primary endpoint: death, MI, urgent target
vessel revascularization, or in-hospital major
bleeding was similar between the bivalirudin
(8.3%) and UFH (8.7%) arms (p = 0.57)
Major bleeding
• Bleeding was significantly reduced with
bivalirudin compared with UFH
UFH
(n = 2,281)
Presented by Dr. Adnan Kastrati at SCAI-ACC i2
Summit/ACC 2008
ISAR-REACT 4
Trial design: Patients with NSTEMI undergoing PCI were randomized to unfractionated
heparin/abciximab (n = 861) vs. bivalirudin alone (n = 860). Follow-up was 30 days.
(p = 0.94)
Results
12
10.9
11.0
• Death, large recurrent MI, urgent target vessel
revascularization (TVR), or major bleeding:
10.9% of the heparin/abciximab vs. 11.0% of the
bivalirudin group (p = 0.94)
%
• Death, any MI, or urgent TVR: 12.8% vs. 13.4%
(p = 0.76)
6
• Major bleeding: 4.6% vs. 2.6% (p = 0.02)
Conclusions
0
Death, large MI, urgent TVR, or
major bleeding
Unfractionated
heparin/abciximab
Bivalirudin
alone
• Among patients with NSTEMI undergoing PCI,
the use of bivalirudin alone results in similar
ischemic events and less bleeding compared
with unfractionated heparin/abciximab
Kastrati A, et al. N Engl J Med 2011;Nov 13:[Epub]
{
ORAL ANTICOAGULANTS
WARIS-II
Warfarin (INR 2.8-4.2) vs. aspirin (160 mg/day) vs. Warfarin ( INR 2.0 -2.5) and
aspirin 75 mg/day for the secondary prevention of myocardial infarction
Primary outcome - composite of death, nonfatal MI or thromboembolic stroke
Major nonfatal bleeding - significantly higher with warfarin compared to aspirin
0.62% Vs 0.17 % (P<0.001)
No Clopidogrel use
ASPECT-2
Low-dose aspirin (n=336) Vs
High-intensity oral anticoagulation (n=325) INR 3 – 4 Vs
Combined low-dose aspirin and moderate intensity oral anticoagulation INR 2 –
2.25 (n=332)
26 months
Primary composite endpoint was first occurrence of MI, stroke or death
Major bleeding was similar in all three groups (<2%)
Minor bleeding was increased in the combination therapy (5% vs. 15%, 3.13 [1.825.37]p=<0.0001)
RE-DEEM
Trial design: After STEMI or NSTEMI, patients on dual antiplatelet therapy were
randomized to dabigatran twice daily: 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406),
150 mg (n = 347), or placebo (n = 371). Follow-up was 6 months.
Results
(p < 0.001)
• Major or clinically significant minor bleeding:
3.5% of the 50 mg group, 4.3% of the 75 mg
group, 7.9% of the 110 mg group, 7.8% of the
150 mg group, and 2.2% with placebo
10
7.9 7.8
• TIMI major bleeding: 0.3%, 0%, 1.2%, 0.3%,
0.3%, respectively
5
4.3
• Cardiovascular death, MI, or stroke: 4.6%,
4.9%, 3.0%, 3.5%, and 3.8% (p = NS),
respectively
3.5
%
2.2
Conclusions
0
Major or clinically significant minor bleeding
50 mg
75 mg
110 mg
• In this phase II trial of patients with STEMI or
NSTEMI, the addition of dabigatran to dual
antiplatelet therapy increased the risk of
bleeding in a dose-dependent manner
• Phase III trials are awaited
150 mg
Placebo
Oldgren J, et al. Eur Heart J 2011;May 7:[Epub]
APPRAISE
Trial design: Patients recovering from an ACS were randomized to apixaban 10 mg daily
(n = 318), apixaban 2.5 mg twice daily (n = 317), or placebo (n = 611). Study medications
were administered for 6 months.
Results
(p = 0.005 for
high dose
vs. placebo)
9
(p = 0.09 for
low dose vs.
placebo)
7.9
•
ISTH major or CRNM bleeding: 7.9% for 10
mg apixaban, 5.7% for 5 mg apixaban, 3%
for placebo
•
Death, MI, recurrent ischemia, or stroke:
6.0%, 7.6%, 8.7% (p = 0.07 for high dose vs.
placebo and p = 0.21 for low dose vs.
placebo), respectively
5.7
6
%
3.0
3
0
major or CRNM bleeding
ISTHISTH
major
or CRNM bleeding
Apixaban
10 mg
Apixaban 5 mg
Conclusions
• This dose-finding study reveals that bleeding
is increased among patients with a recent
ACS with higher doses of apixaban compared
with placebo
• Although this study was not powered for
efficacy, adverse events appeared to be
lowest with 10 mg apixaban
Placebo
APPRAISE Investigators. Circulation 2009;May 26:[Epub]
Apixaban with Antiplatelet Therapy after Acute
Coronary Syndrome APPRAISE 2
• In a randomized trial, patients with an acute coronary syndrome were
assigned to receive apixaban or placebo in addition to standard
therapy.
• The apixaban group had a higher rate of TIMI major bleeding and no
significant reduction in recurrent ischemic events.
Rivaroxaban in Patients with a Recent Acute
Coronary Syndrome ATLAS ACS TIMI 51
• In patients with ACS, low doses of rivaroxaban were effective in
reducing the primary end point of death from cardiovascular causes, MI
or stroke.
• Rivaroxaban also reduced overall mortality although there was more
bleeding.
• Rivaroxaban increased the risk of major bleeding and intracranial
hemorrhage but not the risk of fatal bleeding.
RUBY-1
Trial design: Patients with recent ACS were randomized to receive in a 1:1:1:1:1:1:1
fashion either placebo or darexaban 5 mg BID, 10 mg QD, 15 mg BID, 30 mg QD, 30 mg
BID, or 60 mg QD. Patients were followed for 6 months.
Results
(p = 0.009)
• Primary endpoint (major and clinically relevant nonmajor bleeding) demonstrated a dose-response
relationship for darexaban, with higher bleeding with
BID regimens for the same dose (p = 0.009)
20
• Composite efficacy outcome noted numerically
higher event rates for darexaban as compared with
placebo (4.4% for placebo vs. 3.8% vs. 3.8% vs.
6.3% vs. 6.4% vs. 5.9% vs. 7.8%; p > 0.05).
11.3
10
%
6.8
7.5
5.6
5.6
7.3
3.1
Conclusions
0
Major and clinically relevant bleeding
Placebo
n = 319
30 QD
n = 156
5 BID
n = 159
30 BID
n = 153
10 QD
n = 159
15 BID
n = 159
60 QD
n = 153
• In this phase II trial, darexaban, an oral anti-Xa
agent, was associated with increased bleeding
without an improvement in ischemic outcomes in
patients with ACS already on aspirin and clopidogrel
• Similar results were noted with other anti-Xa agents
such as apixaban
Steg G, et al. Eur Heart J 2011;Aug 30:[Epub]
Thrombin-Receptor Antagonist Vorapaxar in Acute
Coronary Syndromes
• Vorapaxar was not effective in reducing the primary cardiovascular efficacy end
point, and it increased rates of bleeding, including serious bleeding and
intracranial hemorrhage.
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