timi 11a a multicenter trial of the safety and tolerability of two doses of enoxaparin in patients...

TIMI 11ATIMI 11AA Multicenter Trial of the Safety and A Multicenter Trial of the Safety and

Tolerability of Two Doses of Enoxaparin Tolerability of Two Doses of Enoxaparin

in Patients With Unstable Anginain Patients With Unstable Angina

and Non-Q-Wave Myocardial Infarction and Non-Q-Wave Myocardial Infarction

TIMI 11ATIMI 11AA Multicenter Trial of the Safety and A Multicenter Trial of the Safety and

Tolerability of Two Doses of Enoxaparin Tolerability of Two Doses of Enoxaparin

in Patients With Unstable Anginain Patients With Unstable Angina

and Non-Q-Wave Myocardial Infarction and Non-Q-Wave Myocardial Infarction

E Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Design:Design: Multicenter, Open-label, Multicenter, Open-label, Dose-rangingDose-ranging

Size:Size: 630 patients630 patients15 centers15 centers

Countries:Countries: USA and CanadaUSA and Canada

Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

Dose 2

N=309

Dose 1

N=320

IV BolusIV Bolus IV BolusIV Bolus Wgt AdjWgt AdjWgt AdjWgt Adj Fixed DoseFixed DoseFixed DoseFixed Dose

30 mg30 mg

30 mg30 mg

1.25 mg/kg1.25 mg/kg

Q 12 h (2-8d)Q 12 h (2-8d)

1.0 mg/kg1.0 mg/kg

Q 12 h (2-8d)Q 12 h (2-8d)

< 65 kg< 65 kg >> 65 kg 65 kg

40 mg40 mg 60 mg60 mg

Q12 hQ12 h

40 mg40 mg 60 mg60 mg

Q12 hQ12 h

Total Rx Period = 14 days

< 65 kg< 65 kg >> 65 kg 65 kg

Hospital Phase Home Rx

TIMI 11AProtocol Design


PrimaryPrimary

• Evaluate safety and tolerability of two doses of Evaluate safety and tolerability of two doses of

enoxaparin in patients with UA/NQMIenoxaparin in patients with UA/NQMI

SecondarySecondary

• Correlate anti-Xa levels with enoxaparin dose Correlate anti-Xa levels with enoxaparin dose

• Provide preliminary data on clinical outcomes in the Provide preliminary data on clinical outcomes in the

dose tiers evaluateddose tiers evaluated

ObjectivesObjectives


Inclusion Criteria:Inclusion Criteria:• Unstable angina or NQMIUnstable angina or NQMI

– Rest angina > 5 minutesRest angina > 5 minutes

– New onsetNew onset

– Increasing anginaIncreasing angina

• Evidence of CADEvidence of CAD

Exclusion Criteria:Exclusion Criteria:• Recent thrombolytic therapyRecent thrombolytic therapy

• Creatinine > 2 mg/dLCreatinine > 2 mg/dL

• History of heparin-induced thrombocytopeniaHistory of heparin-induced thrombocytopenia


Primary Endpoint:Primary Endpoint:• Major HemorrhageMajor Hemorrhage

overt hemorrhage associated with:overt hemorrhage associated with:

– >3 gm/dL fall in hemoglobin>3 gm/dL fall in hemoglobin

– Intracranial, retroperitoneal, or intraocular Intracranial, retroperitoneal, or intraocular hemorrhagehemorrhage

Secondary Endpoint:Secondary Endpoint:• Anti-Xa levelsAnti-Xa levels

• Death, MI, recurrent ischemia leading to revascularizationDeath, MI, recurrent ischemia leading to revascularization


Incidence of Major HemorrhageIncidence of Major Hemorrhage

Dose Tier 1Dose Tier 11.25 mg/kg1.25 mg/kg

(n=321)(n=321)

InstrumentedInstrumentedSpontaneousSpontaneous

6.5%6.5%

1.9%1.9%

Dose Tier 2Dose Tier 21.0 mg/kg1.0 mg/kg(n=309)(n=309)

00

22

44

66

88

1010

%

of

Pat

ient

s%

of

P

atie

nts

Through Day 14Through Day 14


Incidence of Major Hemorrhage Incidence of Major Hemorrhage

In-Hospital Period OnlyIn-Hospital Period Only

Dose Tier 1Dose Tier 11.25 mg/kg1.25 mg/kg

(n=321)(n=321)

InstrumentedInstrumentedSpontaneousSpontaneous

5.6%5.6%

1.3%1.3%

Dose Tier 2Dose Tier 21.0 mg/kg1.0 mg/kg(n=309)(n=309)

00

22

44

66

88

1010

%

of

Pat

ient

s%

of

P

atie

nts


Summary of Major Event Incidence After Adjudication Summary of Major Event Incidence After Adjudication

from Initial Hospitalization to Day 14from Initial Hospitalization to Day 14

Primary Efficacy OutcomePrimary Efficacy Outcome 18 (5.6%)18 (5.6%) 16 (5.2%)16 (5.2%)(death, MI, recurrent angina)(death, MI, recurrent angina)

Secondary OutcomeSecondary Outcome 14 (4.4%)14 (4.4%) 11 (3.6%)11 (3.6%)(death, MI)(death, MI)

DeathDeath 7 (2.2%)7 (2.2%) 2 (0.6%)2 (0.6%)

Non-fatal MINon-fatal MI 7 (2.2%)7 (2.2%) 9 (2.9%)9 (2.9%)

Recurrent Angina Recurrent Angina Requiring RevascularizationRequiring Revascularization 4 (1.2%)4 (1.2%) 5 (1.6%)5 (1.6%)

1.25 mg/kg1.25 mg/kg 1.0 mg/kg1.0 mg/kg

(n = 321)(n = 321) (n = 309)(n = 309)

All Treated PatientsAll Treated Patients


N=3211.25 mg/kg

Instrumented

Spontaneous

6.5%

1.9%

T3B Hep + Plac

N=735

3.2%

N=3091.0 mg/kg

0

2

4

6

8

10

Dose Tier 1 Dose Tier 2

%

TIMI 11 A Investigators. JACC 29: 1474,1997

TIMI 11APrimary Results

Incidence of Major Hemorrhage thru 14 days

11

22

33

44

55

66

00 22 44 66 88 1010 1212 1414 1616 1818 2020DaysDays

% D

eath

/ M

I /

Rec

. Is

ch.

% D

eath

/ M

I /

Rec

. Is

ch.

Weight-Weight-adjustedadjusteddosedose

Fixed doseFixed dose

5.6%5.6%

5.2%5.2%

1.25 mg/kg (n=321)1.25 mg/kg (n=321)

1.0 mg/kg (n=309)1.0 mg/kg (n=309)

Probability of Cardiovascular EventsProbability of Cardiovascular EventsDeath / MI / Rec Isch req. RevascDeath / MI / Rec Isch req. Revasc


Steady-State Anti-Xa Levels in Patients with Steady-State Anti-Xa Levels in Patients with Unstable AnginaUnstable Angina

Ant

i-Xa

(IU

/ml)

Ant

i-Xa

(IU

/ml)

3rd dose 3rd dose Last Last dose dose

3rd dose 3rd dose Last Last dosedose

1.25 mg/kg1.25 mg/kg 1.0 mg/kg1.0 mg/kg

TroughTroughPeakPeak

00

0.40.4

0.80.8

1.21.2

1.61.6

0.50.5

11

0.60.6

1.11.1

0.60.6

1.51.5

0.80.8

1.61.6


p = 0.006

0.4%0.3%

5.8%5.6%

0

1

2

3

4

5

6

7

All Patients Rapid cTnT Neg

p = 0.001

Mor

tali

ty a

t 1

4 D

ays

(%)

<1.55 mg/dL

>=1.55 mg/dL

CRP Concentration

N = 437 N = 346

TIMI 11ARisk Stratification

Baseline C-reactive Protein and Mortality

Morrow et al. JACC 1998;31:1460-5

ConclusionsConclusionsAcute PhaseAcute Phase

• Enoxaparin 1.0 mg/kg SQ q 12 H associated with a low Enoxaparin 1.0 mg/kg SQ q 12 H associated with a low

rate of major hemorrhage comparable to historical rates rate of major hemorrhage comparable to historical rates

of heparin in similar cohortsof heparin in similar cohorts

Anti-Xa activityAnti-Xa activity

• Dose-related increaseDose-related increase

• No accumulation after multiple dosesNo accumulation after multiple doses

Cardiovascular event rates are comparable in both dose tiersCardiovascular event rates are comparable in both dose tiersE Antman et al for the TIMI 11 A Investigators. JACC 1997:29: 1474

TIMI 11BTIMI 11B

The Effectiveness and Safety of The Effectiveness and Safety of Subcutaneous Enoxaparin Subcutaneous Enoxaparin Compared to Intravenous Compared to Intravenous

Unfractionated Heparin for Patients Unfractionated Heparin for Patients Presenting with Unstable Angina or Presenting with Unstable Angina or

Non-Q-wave MI: An International Non-Q-wave MI: An International Double-blind, Randomized, Parallel Double-blind, Randomized, Parallel

Group, Multicenter StudyGroup, Multicenter StudyAntman et al, Circulation 1999 Oct 12;100(15):1593-601

Design:Design: Randomized, Double-blind, Placebo-Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicentercontrolled, Parallel Group, Multicenter

Size:Size: 4020 patients4020 patients 180 centers 180 centers

Countries:Countries: N. AmericaN. America S. AmericaS. America EuropeEuropeCanadaCanada ArgentinaArgentina SpainSpainUSAUSA UruguayUruguay FranceFrance

ChileChile GermanyGermanyNetherlandsNetherlandsUKUK

Antman et al, Circulation 1999 Oct 12;100(15):1593-601

PrimaryPrimary

• To demonstrate that uninterrupted enoxaparin SQ To demonstrate that uninterrupted enoxaparin SQ over 43 days is superior to UFH IV (72 H) over 43 days is superior to UFH IV (72 H) followed by aspirin alonefollowed by aspirin alone

SecondarySecondary

• Cost-effectiveness comparison of the different Cost-effectiveness comparison of the different treatment armstreatment arms

ObjectivesObjectives


• Rest unstable angina or NQMIRest unstable angina or NQMI

• ST deviation > 0.5 mm or positive ST deviation > 0.5 mm or positive

serum cardiac markersserum cardiac markers

Inclusion CriteriaInclusion Criteria


• Physician planning revascularization within 24 hours Physician planning revascularization within 24 hours

• Angina related to an evolving Q-wave MI angina Angina related to an evolving Q-wave MI angina

precipitated by secondary causes precipitated by secondary causes

(e.g., tachydysrhythmia, etc.)(e.g., tachydysrhythmia, etc.)

• CABG within 2 months, mechanical intervention CABG within 2 months, mechanical intervention

within within

6 months6 months

• History of heparin-induced thrombocytopeniaHistory of heparin-induced thrombocytopenia

Exclusion CriteriaExclusion Criteria


Primary EndpointPrimary Endpoint - Efficacy - Efficacy• Death, MI, recurrent ischemia requiring urgent Death, MI, recurrent ischemia requiring urgent

revascularization at study day 43revascularization at study day 43

Primary EndpointPrimary Endpoint - Safety - Safety• Major hemorrhage at study day 43Major hemorrhage at study day 43

– DeathDeath

– Transfusion of >2 units packed bloodTransfusion of >2 units packed blood

– > 3 gm/dL fall in hemoglobin> 3 gm/dL fall in hemoglobin

– Intracranial, retroperitoneal, or intraocular hemorrhageIntracranial, retroperitoneal, or intraocular hemorrhageAntman et al, Circulation 1999 Oct 12;100(15):1593-601

ENOXENOX Bolus 30 mg IVBolus 30 mg IV1.0 mg / kg Q12h1.0 mg / kg Q12h

Pt. with UA/NQMI Pt. with UA/NQMI << 24 h 24 h

Primary Endpoint:

UFH UFH >> 3 days 3 daysBolus 70 U / kgBolus 70 U / kg

INF 15 U / kg / hINF 15 U / kg / h

Major BleedingSerious AEs

ASAASA

aPTT 1.5-2.5 x aPTT 1.5-2.5 x controlcontrol

Hosp DC Hosp DC (or 8 days)(or 8 days)

TIMI 11BProtocol Design

Death, MI, Urgent Revascularization

Acute Phase Protocol


22

44

66

88

1010

1212

1414

1616

1818

2020

00 22 44 66 88 1010 1212 1414

P=0.029RRR 15 %

UFHUFHENOXENOX 16.7 %16.7 %

14.2 %14.2 %%

Days

14.5 %14.5 %

12.4 %12.4 %

P=0.048RRR 15 %

TIMI 11BPrimary Results

Death/MI/Urgent Revascularization at 14 Days

E. Antman for The TIMI 11B Investigators Circulation 1999.

0

1

2

3

4

5

6

7

8

9

0 8 16 24 32 40 48 56 64 72

% P

ts

UFHUFHENOXENOX

5.2 %5.2 %

4.2 %4.2 % RRR 18%RRR 18%P=0.20P=0.20

7.3 %7.3 %

5.5 %5.5 %

RRR 24%RRR 24%P=0.02P=0.02

ESSENCEESSENCE

TIMI 11 BTIMI 11 B

Hours from Randomization

Efficacy ResultsDeath/MI/Urgent Revasc. Early Rx Phase

TIMI 11B


Efficacy ResultsTIMI 11B

- ESSENCE Meta-Analysis- ESSENCE Meta-Analysis

OVERALL

ESSENCE

TIMI 11B

OVERALL

ESSENCE

TIMI 11B

OVERALL

ESSENCE

TIMI 11B

0.5 1 2

Day

8

14

43

0.6 0.7 0.8 0.9Odds RatioEnox Better UFH Better

OR % p

0.77(0.62-0.95)

23 0.02

0.79(0.65-0.96)

21 0.02

0.82(0.69-0.97)

18 0.02

N

7081

7081

7081

3910

3910

3910

3171

3171

3171

UFH(%)

Enox (%)

5.3 4.1

6.5 5.2

8.6 7.1

Death/MI

Antman E, Cohen M for The TIMI 11B & ESSENCE Investigators Circulation 1999.

Pt. with UA/NQMI < 24 h

Death, MI, Severe Rec Isch Requiring Urgent Revasc

Acute = Day 8UFH iv > 72 hUFH iv > 72 h

Major Bleeding Serious AEs

ASA

ENOX iv-b,scENOX iv-b,sc

Placebo scPlacebo sc ENOX scENOX sc Chronic = Day 43

TIMI 11BProtocol Design


DaysDays

0

2

4

6

8

10

12

14

16

18

20

0 4 8 12 16 20 24 28 32 36 40 44

P=0.048P=0.048RRR 12 %RRR 12 %

UFHUFHENOXENOX

19.7 %19.7 %

17.3 %17.3 %

%%

TIMI 11BPrimary Results: Chronic Phase

Death/MI/Urgent Revascularization at 43 Days


TIMI 11BEfficacy Results

Efficacy of Enoxaparin Stratified by Baseline Risk

0.5 1 2

High(N=593)

Inter(N=1645)

Low(N=1672)

UFH(%)

ENOX(%)

OR (95 CI)

Favors ENOX

Favors UFHO.R.

29.6 0.78 (0.55,1.13)24.8

20.5 17.9

15.0 14.1

0.85 (0.66,1.08)

0.94 (0.72,1.23)

22

15

6

%

P=0.079 trend

Day 43 Death/MI/UR at 43 DaysDeath/MI/UR at 43 Days

Holper E. AHA 1998

TIMI 11BEfficacy Results

Efficacy of Enoxaparin Stratified by Rx Strategy

6.17.1

0

2

4

6

8

10

UFH ENOX

%

8.8

7

0

2

4

6

8

10

UFH ENOX

7.6 7.9

0

2

4

6

8

10

UFH ENOX

Med Rx

Guzman ESC 1999

PCI CABG

OR (95 CI) 0.85 (0.62,1.16) 0.77 (0.45,1.31) 1.04 (0.55,1.95)

1286 265 275 396 3741314

D/MI/UR

timi 11a a multicenter trial of the safety and tolerability of two doses of enoxaparin in patients...

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