Slide 1
AGGRASTATAGGRASTAT™™†† (tirofiban, MSD)(tirofiban, MSD) to ZOCORto ZOCOR™™†† (simvastatin, MSD)(simvastatin, MSD)
(A to Z) Trial(A to Z) Trial
Results from the Results from the AAGGRASTAT GGRASTAT PhasePhase
†Trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Slide 2
BackgroundBackground
• Enoxaparin, a LMWH, has been shown to be superior to UFH in ACS populations in the absence of GP IIb/IIIa inhibitors– Most trials used conservative management and
predated widespread use of GP IIb/IIIa inhibitors
• GP IIb/IIIa inhibitors are recommended for high-risk ACS patients in whom an invasive strategy is planned
• Small trials suggest additional benefit of enoxaparin over UFH when used in combination with GP IIb/IIIa inhibitors
LMWH=low-molecular-weight heparin; UFH=unfractionated heparin; ACS=acute coronary syndrome; GP=glycoprotein
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Trial ObjectivesTrial Objectives
A-Phase• To assess the safety profile and efficacy of
enoxaparin compared with UFH in patients with NSTE ACS who received concomitant therapy with AGGRASTAT™† (tirofiban, MSD) and ASA
Z-Phase• To evaluate the efficacy and tolerability of early
use of aggressively-dosed treatment with ZOCOR™† (simvastatin, MSD) compared with an accepted care regimen
NSTE=non–ST-elevation; ASA=acetylsalicylic acid
Adapted from Blazing MA et al Am Heart J 2001;142(2):211–217; Blazing MA et al JAMA 2004;292(1):55–64.†Trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA.
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Participating CountriesParticipating Countries
340 enrolling sites in 41 countries
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
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Eligibility CriteriaEligibility Criteria
• Inclusion criteria– Chest pain at rest for 10 minutes– Dynamic ST changes of at least 0.5 mm or positive
cardiac marker (troponin, CK-MB, or CK 2 ULN)– 21 to 80 years of age
• Major exclusion criteria– Prior use of statin or other lipid-lowering agent– Use of GP IIb/IIIa agent other than AGGRASTAT™†
(tirofiban, MSD)– >24 hours of prior UFH or >2 doses enoxaparin– High risk of bleeding, prior thrombocytopenia– Abnormal creatinine and ALT/AST values
CK-MB=creatine phosphokinase muscle band; ULN=upper limits of normal; ALT=alanine aminotransferase;AST=aspartate aminotransferase
Adapted from Blazing MA et al Am Heart J 2001;142(2):211–217; Blazing MA et al JAMA 2004;292(1):55–64.†Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Slide 6
A-Phase Study DesignA-Phase Study Design
30 days
Randomize
–24 hr
Chest pain
AGGRASTAT™†
(tirofiban, MSD)
+ ASA
Invasive or conservativecare per local practice
n=2026
n=1961
Enoxaparin1 mg/kg q12h
UFHWeight-adjusted
Z
Z
Treat and evaluate for Z-Phase
n=2018
n=1952
N=3987
Primary endpoint
UA/NSTEMI=unstable angina/non–ST-elevation myocardial infarction
Adapted from Blazing MA et al Am Heart J 2001;142(2):211–217; Blazing MA et al JAMA 2004;292(1):55–64.†Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
NSTEACS
Final A-Phase
visit
7 days
Min 0 hr Max120 hr
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A-Phase Trial Design and A-Phase Trial Design and Safety ProfileSafety Profile
• Selection of management strategy (invasive or conservative) left to investigator at randomization
– Crossover from enoxaparin to UFH allowed for invasive procedures
• Bleeding events recorded via two methods
– Investigator assessment on case record form and independent review of hemoglobin values
– Units of packed red blood cells transfused
– Bleeding events categorized by change in hemoglobin levels using TIMI criteria
TIMI=Thrombolysis In Myocardial Infarction
Adapted from Blazing MA et al Am Heart J 2001;142:211–217; Blazing MA JAMA 2004;292(1):55–64.
Slide 8
• Primary– Composite of death, MI, and refractory ischemia
(+ marker and/or ECG changes) within 7 days of start of AGGRASTAT™† (tirofiban, MSD) therapy
• Secondary– Death, MI, refractory ischemia, urgent coronary
revascularization, and DMCMIE evaluated at 7 days individually and as a composite
• Tertiary– All primary and secondary endpoints and readmission
for ACS evaluated at 48 hours and 30 days
Study EndpointsStudy Endpoints
DMCMIE=documented multiple clinical myocardial ischemic events†Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
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Median age (years) 61 61 Men 71.4% 71.2% White 85.6% 85.2%Diabetes 19.5% 18.2%Hypertension 50.0% 52.3%Current smoking 36.0% 39.4%Prior MI 17.8% 18.3%Index MI* 74.5% 72.8%ST change >1 mm 70.3% 71.9%UFH** 37.3% 38.5%LMWH** 34.3% 34.2%
Baseline CharacteristicsBaseline Characteristics
*Investigator determined; **Use before randomization
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
Enoxaparin UFHCharacteristics (n=2026) (n=1961)
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Hospital CourseHospital Course
Enoxaparin UFH(n=2026) (n=1961)
Median study drug administration (hours) 49.1 48.2Planned early aggressive strategy 55.2 55.4PCI or catheterization
at 108 hrs 59.6 61.3Concomitant therapies at discharge
ACEI 43.1 44.1ARB 2.4 3.9ASA 98.9 98.4Beta-blocker 84.9 83.7CCB 21.5 22.9Diuretic 22.0 23.6Nitrate 81.3 84.0
PCI=percutaneous coronary intervention; ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; CCB=calcium channel blocker
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
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Primary Endpoint—OverallPrimary Endpoint—Overall
0 10 20 30
UFH (n=1952)Enoxaparin(n=2018)
Days from enrollment
Pri
mar
y en
dp
oin
t (%
)
5 15 250
2
4
6
8
10
12
8.4% (169 events)
9.4% (184 events)
HR 0.88 (95% CI, 0.71–1.08)
HR=hazard ratio; CI=confidence interval
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
Composite of death, MI, and refractory ischemia
7
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Secondary Endpoints at 7 DaysSecondary Endpoints at 7 Days
DMCMIE=documented multiple clinical myocardial ischemic events
*Indicates chest pain requiring change in therapy but not meeting criteria for refractory ischemia
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
Secondary composite 12.7 14.2 0.89 0.75–1.05
Death 1.1 0.9 1.26 0.67–2.38
MI 3.6 4.4 0.82 0.60–1.13
Refractory ischemia 4.1 4.9 0.82 0.61–1.10
Urgent revascularization 5.1 5.2 0.98 0.74–1.29
DMCMIE* 1.1 1.9 0.58 0.34–0.98
% of PatientsEnoxaparin UFH HR 95% CI
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Subgroup AnalysesSubgroup Analyses
Enoxaparin UFH
6.4 7.411.3 12.5
8.4 9.4
8.4 10.78.3 9.2
8.8 8.57.7 10.6
Primary hypothesis
<65 years65 years
DiabetesNo diabetes
InvasiveConservative
Age
% of PatientsHR (95% CI)
0.5 1 1.5
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
Favors enoxaparin Favors UFH
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Subgroup AnalysesSubgroup Analyses (continued) (continued)
Primary hypothesis
No ST changeST change (1 mm)
Elevated troponin (>ULN)Normal troponin
5–7
8.4 9.4
7.1 6.88.9 10.6
8.3 9.58.1 8.0
6.4 5.78.1 10.2
15.1 17.9
0–23–4
Enoxaparin UFH% of Patients
TIMI risk score
HR (95% CI)
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
0.5 1 1.5Favors enoxaparin Favors UFH
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0
1
2
3
4
5
24-Hour Bleeding Events24-Hour Bleeding Events
TIMI major=hemoglobin drop >5 mg/dL, intracranial bleed, or pericardial bleedTIMI minor=hemoglobin drop >3 or 5 mg/dL with an identified site; hemoglobin drop >4 or 5 mg/dL without an identified site or hematuria, hematochezia, or hematemesis
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.
% o
f P
atie
nts
TIMI major TIMI majoror minor
Transfusion
0.40.9
2.2
3.0
0.81.0
p=0.05
UFH(n=1965)
Enoxaparin(n=1940)
UFH(n=1965)
Enoxaparin(n=1940)
UFH(n=1965)
Enoxaparin(n=1941)
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ConclusionsConclusions
• In patients with high-risk NSTE-ACS treated with AGGRASTAT™† (tirofiban, MSD) and ASA, enoxaparin is an effective noninferior alternative to UFH
• Overall rates of bleeding, transfusion, and thrombocytopenia were low in both heparin groups given AGGRASTAT and ASA
Adapted from Blazing MA et al JAMA 2004;292(1):55–64.†Trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Slide 17
ReferencesReferences
Slide 18
A-Phase of the AGGRASTATA-Phase of the AGGRASTAT™™†† (tirofiban, MSD)(tirofiban, MSD) to ZOCORto ZOCOR™™†† (simvastatin, MSD) (A to Z) Trial(simvastatin, MSD) (A to Z) Trial
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Merck does not recommend the use of any productin any different manner than as described
in the prescribing information.
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†Trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA.