Review of Evidence Antithrombotics in Non ST Elevation ACS by hcj

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									   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. standard-

dose (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
Cumulative Kaplan–Meier Estimates of the Rates of Key Study End 
Points during the Follow-up Period
                                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.
                                            Results
      Death, MI, or           Major
                                            • CV death, MI or stroke ↓ with prasugrel vs
        stroke               Bleeding
         HR 0.81                            clopidogrel (Figure)
                              HR 1.32
         p < 0.001            p = 0.03      • 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
        Prasugrel           Clopidogrel     • 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
                                                      •   Death from vascular cause, MI, stroke lower
                                                          in ticagrelor arm, including in patients
         (p < 0.001)      10         (p < 0.001)          undergoing PCI
30
                                                      •   Mortality, stent thrombosis (p = 0.02) ↓
                                                          with ticagrelor; stroke rate similar (p = 0.22)
20                                        5.9         •   No increase in fatal bleeding or overall
                                                          major bleeding, but higher rate of non-
                          %5        4.5                   CABG major bleeding (p = 0.03)
%                11.7
          9.8
10
                                                      Conclusions
                                                      • Ticagrelor superior to clopidogrel for several
0                          0                            outcomes including death, MI, and stent
                                                        thrombosis in patients presenting with ACS
       Primary endpoint        All-cause mortality
                                                      • Very promising results; reduction in CV mortality
           Ticagrelor                 Clopidogrel       notable in the modern era of ACS
           (n = 9,333)                (n = 9,291)
                                                      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 300-
    600 mg, then 75 mg daily (n = 208).

                                                         Results
                          (p = NS)
                                                         •      No TIMI major bleeds in any group
                                                         •      Numerical increase in access bleeds requiring
6                                                               medical attention with higher doses of
                                                                elinogrel compared with clopidogrel
%                                                        •      Death, MI, stroke, or revascularization:
                           4.0                                  approximately 2.8% of the elinogrel 150 mg
                                                                group, 4% of the elinogrel 100 mg group, and
                   2.8
                                                                1.5% of the clopidogrel group (p = NS)
3                                                        •      Dyspnea: 12.1%, 15.4%, and 4.3%

                                     1.5
                                                         Conclusions
                                                             • Among patients undergoing nonurgent PCI, the use
0                                                              of elinogrel is feasible
           Death, MI, stroke, or revascularization
                          ischemic
                                                             • Access site bleeds were numerically higher with
                                                               increasing doses of elinogrel
       Elinogrel         Elinogrel         Clopidogrel
       150 mg            100 mg                              • 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.

                                                               Results
        (p < 0.001)                     (p = 0.015)
                                                               •    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      57.2                 60
                                        48.4
                42.1      %                                    Conclusions
% 40                       40                  35.7
                                                               • Cilostazol was associated with greater reduction in
                                                                 platelet activity compared with high-dose
 20                           20                                 clopidogrel in patients with high platelet reactivity
                                                               • Clinical endpoints were not available; long-term
  0                            0
  MPA reduction with                                             outcomes need to be assessed as well
                                   % platelet inhibition
  20 μmol/L ADP
   Cilostazol + clopidogrel           High-dose clopidogrel
   (n = 30)                           (n = 30)                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
   Review of Evidence
Antithrombotics in Non ST Elevation
               ACS
                 ￿

             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




                                            Freedom from Death/MI
                                                                    0.95




                                                                    0.9




                                                                    0.85
                                                                               Enoxaparin

                                                                               UFH
                                                                    0.8

                                                                           0    5        10     15      20    25   30

                                                                                    Days from Randomization



                                                                                 Kaplan Meier Curve

Absolute Risk Reduction   0.5
Hazard Ratio              0.96
95% CI                    0.86–1.06
p                         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

             6             5.7       5.8                                                                                  Enoxaparin
             5                                                                                                            Fondaparinux
                                                               4.1
             4

             3
                                                                           2.2
             2

             1

             0
                 OASIS 5 Death, MI, or refractory      OASIS 5 Major bleeding at 9        OASIS 5 Composite primary
                      ischemia at 9 days                         days                   outcome and major bleeding at 9 days

Absolute Risk Reduction          -0.1                                1.9                         1.7
Hazard Ratio                     1.01                                0.52                        0.81
Confidence Interval              0.90–1.13                           0.44–0.61                   0.73–0.89
p                                0.007*                              < 0.001†                    < 0.001†

*p for noninferiority; †p for superiority. Yusuf S, et al. N Engl J Med 2006;354:1464–76.
                           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).

                                                        Results
           (p = 0.27)             (p = 0.06)            •   Major bleeds/minor bleeds/vascular access
                                                            site complications at 48 hours: 4.7% of the
                  5.8                                       low-dose heparin group vs. 5.8% of the
6                                                           standard-dose heparin group (p = 0.27)
            4.7                  4.5
                                                        •   Death, MI, or revascularization: 4.5% vs. 2.9%
%                                                           (p = 0.06), respectively
                                                        •   Stent thrombosis: 1.2% vs. 0.5% (p = 0.11),
                                         2.9                respectively
3

                                                        Conclusions
                                                        • Among ACS patients initially treated with
                                                          fondaparinux, PCI can be safely performed with the
0
                                                          addition of unfractionated heparin
      Major/minor bleed,
            bleeding                outcome
                                Death, MI, or
         or vascular          revascularization         • Low-dose and standard-dose heparin had the same
        complication                                      frequency of bleeding events
                                                        • Low-dose heparin therapy was associated with a
          Low-dose               Standard-dose
                                                          marginally significant increase in ischemic events
          heparin                heparin
                                                      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   11.8
              12



              10



               8                  7.7
                          7.3

                                                                                        UFH or Enoxaparin + GP IIb/IIIa
               6                              5.7
                                                       5.3
                                                                                        Bivalirudin + GP IIb/IIIa

               4



               2



               0
                      ACUITY Composite ACUITY Major bleeding at   ACUITY Net clinical
                   ischemia endpoint at 30    30 days             outcome at 30 days
                           days
Absolute Risk Reduction         -0.4                0.4              -0.1
Hazard Ratio                    1.07                0.93             1.01
95% CI                          0.92–1.23           0.78–1.10        0.90–1.12
p                               0.007*              < 0.001*         < 0.001*
             ACUITY Composite Ischemia & Bleeding
                         Outcomes
                 10
                                                                                      9.1
                  9


                  8                  7.8
                              7.3                     7.3
                                                             7.0               7.1
                  7
                                                                                                                            UFH + GP IIb/IIIa
                  6                                                                                    5.7

                  5                                                                                                          Bivalirudin alone
                  4

                                                                                                              3.0
                  3


                  2


                  1


                  0
                      ACUITY Composite ischemia Ischemia endpoint by       Ischemia endpoint by      ACUITY Major bleeding at 30
                          endpoint at 30 days   thienopyridine loading thienopyridine loading before        days
                                                before angiography or angiography or PCI No
                                                PCI YES
Absolute Risk Reduction          -0.5                   0.3 -2.0        2.7
Hazard Ratio                     1.08                   0.97            1.29                          0.53
95% CI                           0.93–1.24              0.80–1.17       1.03–1.63                     0.43–0.65
p                                0.32                       0.054 (for interaction)                         < 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
                                                      • Primary endpoint: death, MI, urgent target
           (p = 0.57)                (p = 0.008)        vessel revascularization, or in-hospital major
                                                        bleeding was similar between the bivalirudin
 10       8.3 8.7              5      3.1 4.6           (8.3%) and UFH (8.7%) arms (p = 0.57)
  9                                                   • Bleeding significantly ↓ with bivalirudin
  8                            4                        compared with UFH: major (33%), minor (31%)
  7
  6                            3                      Conclusions
%5                            %
  4                            2                      • Bivalirudin is not superior to UFH as adjunct
  3                                                     anticoagulation therapy for troponin-negative
  2                            1                        patients undergoing PCI, who were pretreated
                                                        with 600 mg of clopidogrel
  1
  0                            0                      • Bleeding was significantly reduced with
      Composite endpoint           Major bleeding       bivalirudin compared with UFH

                Bivalirudin            UFH
                (n = 2,289)         (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)

    6                                             • Death, any MI, or urgent TVR: 12.8% vs. 13.4%
                                                    (p = 0.76)
                                                  • Major bleeding: 4.6% vs. 2.6% (p = 0.02)


    0                                             Conclusions
         Death, large MI, urgent TVR, or          • Among patients with NSTEMI undergoing PCI,
                 major bleeding                     the use of bivalirudin alone results in similar
                                                    ischemic events and less bleeding compared
        Unfractionated              Bivalirudin     with unfractionated heparin/abciximab
        heparin/abciximab           alone

                                                   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 [1.82-
5.37]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.

                        (p < 0.001)               Results
     10                                           • Major or clinically significant minor bleeding:
                                                    3.5% of the 50 mg group, 4.3% of the 75 mg
                        7.9 7.8                     group, 7.9% of the 110 mg group, 7.8% of the
                                                    150 mg group, and 2.2% with placebo
                                                  • TIMI major bleeding: 0.3%, 0%, 1.2%, 0.3%,
                                                    0.3%, respectively
      5           4.3
            3.5                                   • Cardiovascular death, MI, or stroke: 4.6%,
    %                                               4.9%, 3.0%, 3.5%, and 3.8% (p = NS),
                                   2.2              respectively

                                                  Conclusions
        0
                                                  • In this phase II trial of patients with STEMI or
Major or clinically significant minor bleeding      NSTEMI, the addition of dabigatran to dual
                                                    antiplatelet therapy increased the risk of
                                                    bleeding in a dose-dependent manner
        50 mg            75 mg           110 mg
                                                  • 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          (p = 0.09 for           •    ISTH major or CRNM bleeding: 7.9% for 10
            high dose vs.          low dose vs.                  mg apixaban, 5.7% for 5 mg apixaban, 3%
              placebo)                placebo)                   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.
                7.9                                              placebo), respectively
                             5.7
%                                                    Conclusions
                                        3.0
                                                     • This dose-finding study reveals that bleeding is
                                                       increased among patients with a recent ACS with
                                                       higher doses of apixaban compared with placebo
              ISTH major or CRNM bleeding
                                                     • Although this study was not powered for efficacy,
         Apixaban                                      adverse events appeared to be lowest with 10 mg
                             Apixaban 5 mg             apixaban
          10 mg
                             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 non-
      20                                                             major bleeding) demonstrated a dose-response
                                                                     relationship for darexaban, with higher bleeding with
                                                                     BID regimens for the same dose (p = 0.009)
                                                                   • Composite efficacy outcome noted numerically
                                          11.3                       higher event rates for darexaban as compared with
     10                                                              placebo (4.4% for placebo vs. 3.8% vs. 3.8% vs.
%                 6.8         7.5                7.3
                        5.6         5.6                              6.3% vs. 6.4% vs. 5.9% vs. 7.8%; p > 0.05).
            3.1
                                                                     Conclusions
      0                                                            • In this phase II trial, darexaban, an oral anti-Xa agent,
          Major and clinically relevant bleeding                     was associated with increased bleeding without an
                                                                     improvement in ischemic outcomes in patients with
    Placebo          5 BID                10 QD          15 BID      ACS already on aspirin and clopidogrel
    n = 319         n = 159               n = 159        n = 159
                                                                   • Similar results were noted with other anti-Xa agents
          30 QD               30 BID                60 QD            such as apixaban
          n = 156             n = 153               n = 153
                                                                    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.
          ATLAS ACS 2-TIMI 51: Design
                     Recent ACS: STEMI, NSTEMI, UA
              No increased bleeding risk, no warfarin, no ICH, no prior
                         stroke if on ASA + thienopyridine
                          Stabilized 1-7 days after index event
                                                                                + ASA 75 to
                  Stratified by thienopyridine use at MD discretion             100 mg/day

                                RIVAROXABAN                       RIVAROXABAN
      Placebo                         2.5 mg BID                       5.0 mg BID
        n = 5176
                                       n = 5174                          n = 5176
 ASA + Thieno, n = 4821
                                ASA + Thieno, n = 4825            ASA + Thieno, n = 4827
     ASA, n = 355
                                    ASA, n = 349                      ASA, n = 349

PRIMARY ENDPOINT:
 EFFICACY: CV death, MI, stroke*
 SAFETY: TIMI major bleeding not associated with CABG
         Event-driven trial of 1002 events in 15,342 patients
                           ATLAS ACS 2-TIMI 51: Efficacy Endpoint

                                                                    Placebo
                                     HR, 0.84 (95% CI, 0.74-0.96)
                                               P = .002                 Pooled rivaroxaban
CV Death, MI, Stroke (%)




                                    Placebo         Pooled 2.5 mg and
                                                     5.0 mg BID doses
                               ATLAS ACS 2-TIMI 51: 2.5 mg BID

                                P = .002
                                NNT = 63
Proportion of Population (%)




                                           P = .002    P =.002
                                           NNT = 71   NNT = 63
                       ATLAS ACS-TIMI 51: Stent Thrombosis
Stent Thrombosis (%)




                            47/5115




       ARC = Academic Research Consortium
                 ATLAS ACS 2-TIMI 51: Bleeding

                     P < .001
Population (%)




                                          P = .009
                                                              P = .66




                         P values for both doses vs placebo
                                           Diagnosis of UA/NSTEMI is Likely or Definite


                                                      ASA (Class I, LOE: A)
                                          Clopidogrel if ASA intolerant (Class I, LOE: B)


                                                    Select Management Strategy



            Initial Conservative Strategy or Unknown                                             Invasive Strategy†


      Initiate anticoagulant therapy (Class I, LOE: A)
                                                                              Initiate anticoagulant therapy (Class I, LOE: A)*
      Acceptable options include
                                                                              Acceptable options include
      • Enoxaparin or UFH (Class I, LOE: A)
                                                                              • Enoxaparin or UFH (Class I, LOE: A)
      • Fondaparinux (Class I, LOE: B)*
                                                                              • Bivalirudin (Class I, LOE: B)
      • Enoxaparin or fondaparinux preferred over UFH
      (Class IIa, LOE: B)

                                                                          Precatheterization: Add second antiplatelet agent (Class I, LOE: A)‡
                                                                          • Clopidogrel (Class I, LOE: B) or
                                                                          • GP IIb/IIIa inhibitor (Class I, LOE: A)
               Initiate clopidogrel (Class I, LOE: B)                     • (IV eptifibatide or tirofiban preferred)
                                                                          Next step per triage decision at angiography

*If fondaparinux is used with an invasive 
strategy (Class I, LOE: B), it must be 
coadministered with another anticoagulant with     CABG:                       PCI: Class I:                                              Medical
Factor IIa activity, i.e., UFH.)                   Maintenance ASA             • Clopidogrel (if not begun                                Therapy: D/C
†Timing of invasive strategy generally is          (Class I, LOE: A)           precatheterization) (LOE: A) or                            GP IIb/IIIa
assumed to be 4 to 48 hours. If immediate                                      • Prasugrel (LOE: B) or                                    inhibitors if
angiography is selected, see STEMI guidelines.                                 • Selectively, a GP IIb/IIIa inhibitor (if not             begun and give
‡Precatheterization  triple antiplatelet therapy                               begun precatheterization) (LOE: A)                         clopidogrel per
(ASA, clopidogrel, GP inhibitors) is a Class IIb,                                                                                         conservative
LOE: B  rec for selected high-risk patients.       Wright RS, et al. J Am Coll Cardiol. 2011;57(19):1920-59.                              strategy
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