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

Slide 3

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.

Slide 4

Participating CountriesParticipating Countries

340 enrolling sites in 41 countries

Adapted from Blazing MA et al JAMA 2004;292(1):55–64.

Slide 5

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

Slide 7

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.

Slide 9

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)

Slide 10

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.

Slide 11

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

Slide 12

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

Slide 13

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

Slide 14

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

Slide 15

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)

Slide 16

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

Before prescribing, please consult manufacturers’ prescribing information.

Merck does not recommend the use of any productin any different manner than as described

in the prescribing information.

Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.All rights reserved. 9-07 ARS 2004-W-6323-SS Printed in USA

VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com

†Trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA.