thrombin receptor antagonist in - intranet da sbcintranet.cardiol.br/coberturaonline/slides/tra...

Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombosis

On behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators

NCT00526474; Trial funded by Merck

** CONFIDENTIAL FINAL DRAFT **EMBARGOED UNTIL SAT 3/24 10AM

Protease-activated receptor (PAR)-1

Thrombin

Signal

CC CC CC CC

Vorapaxar

• Vorapaxar is an oral, potent, and selective antagonist of PAR-1

• Metabolism by CYP3A4 enzymes• No meaningful renal clearance• Long half-life (T1/2 > 100 hrs)

Shape ChangeActivation

Aggregation

X

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

TRA Program(38,500 pts)

TRA (Vorapaxar) Program

NSTEACS12,944

2º Prevention~26,500 pts

Vorapaxar Placebo Vorapaxar Placebo

Median F/U 1.4 years

3

Median F/U 2.5 years

• CV Death, MI, Stroke, Hosp for ischemia, Urgent Coronary Revasc. HR 0.92 (0.85, 1.01), p=0.072

• CV Death, MI, StrokeHR 0.89 (0.81, 0.98), p=0.018


Primary Objectives

Primary ObjectiveTo test the hypothesis that vorapaxar will ↓ athero-thrombotic events in stable pts w/ atherosclerosis treated for ≥1 yr in addition to standard therapy.

Parallel Scientific ObjectivesTo test the hypotheses that …1. antagonism of PAR1 is a valuable novel target2. adding a new antiplatelet agent to ASA is

effective for long-term 2° prevention in stable pts


Trial OrganizationTIMI Study GroupEugene Braunwald (Chair) David A. Morrow (PI)BM Scirica, MP Bonaca Stephen D. Wiviott (CEC)Polly Fish Sabina A. Murphy (Statistics)

Worldwide Monitoring TeamsCovance – Jennifer Mead WCT – Lucy BennettICON – Jeroen Kleijne Merck Monitoring

Sponsor: Merck John Strony Gail Berman/Leslie Lipka Ann Killian Xuan Liu, Weili He

Data Safety Monitoring BoardRobert Frye (Chair) Kent R. BaileyJ. Donald Easton Judith HochmanP. Gabriel Steg Freek Verheught


ArgentinaS Ameriso/ E PaolassoAustraliaP Aylward/G HankeyAustria M PichlerBelgiumF van de Werf BrazilJ NicolauCanada P Teal/P TherouxChileR CorbolanColombiaD IsazaCzech Republic J Spinar

National Lead InvestigatorsDenmarkP GrandeFinlandM NieminenFrance JP BassandGermany C Diehm/H DienerHungary R KissIsrael H HodItaly D De Ferrari/P MerliniJapanS GotoNetherlands T Oude Ophius

New ZealandH WhiteNorwayD Nilsen/L ThomassenPoland M TenderaPortugalJ MoraisSouth Africa A DalbySpain A BetriuSwedenM DellborgSwitzerlandH BounameauxUnited Kingdom R Wilcox


Prior MI, CVA, or PAD

Vorapaxar2.5 mg/d

PlaceboRANDOMIZE 1:1 DOUBLE BLIND

Follow up VisitsDay 30, Mo 4, Mo 8, Mo 12

Q6 months

Standard care including oral antiplt rx

Final Visit Event Driven Design

Minimum of1 year of follow-up

Key Inclusion:1) MI: 2 wks - 12 mo 2) Ischemic CVA: 2 wk-12 mo3) PAD: claudication + abnl

ABI or prior revasc

Trial Design

Stratified by:1) Qualifying athero2) Use of thienopyridine


EndpointsEfficacy: hierarchical testing1. Cardiovascular (CV) death, MI, or stroke2. CV death, MI, stroke, or urgent coronary

revascularization 3. CV death or MI

Bleeding endpoints of primary interest:• GUSTO moderate or severe bleeding• TIMI Clinically Significant Bleeding:

TIMI major, TIMI minor, or bleeding requiring medical attention (medical/surgical rx, lab eval)


DSMB Action

January, 2011, the DSMB announced that based on its ongoing review of safety:– ↑ ICH with vorapaxar in pts w/ a prior stroke D/C all pts with a prior stroke

– Trial should continue in pts without a hx of stroke

Analyses• 1st line analysis in all patients, including stroke • 2nd line analysis (new): pts w/out prior stroke• Special interest in patients who qualified w/ MI


EnrollmentEnrolled 9/2007-11/2009: 32 countries, 1032 sites, 26449 patients

32 (0.1%) lost to F/U2.0% withdrew consent for F/U


Baseline Characteristics

Age (yrs, median)≥ 75 yrs (%)

Female (%)

MI (n = 17779, %)PAD (n = 3787, %)Stroke (n = 4883, %)

Qualifying Atherosclerosis

Placebo(N = 13224)

61 (53, 69)1124

671419

Vorapaxar(N = 13225)

61 (53, 69)1124

671418

Any CAD (%)Any prior stroke (%)Diabetes (%)Current smoker (%)eGFR <60 ml/min/1.73 m2

7822252115

7822252116


Background TherapyPlacebo

(N = 13224)Vorapaxar(N = 13225)

Lipid-lowering agent (%)ACEI or ARB (%)Beta-blocker (qualifying MI)

927584

917484

Qualifying MI AspirinThienopyridine

PAD AspirinThienopyridine

Stroke AspirinThienopyridineDipyridamole

Antiplatelet Therapy, %9878

8837

812419

9878

8837

812420

Other Medications at Enrollment


Primary Efficacy EvaluationCV Death, MI, or Stroke

0%

2%

4%

6%

8%

10%

12%

0 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080

Even

t Rat

e (%

)

Days since randomization

9.3%

10.5%

Hazard Ratio 0.87;95% CI 0.80 to 0.94p < 0.001

N = 26449Median f/u2.5 years

PlaceboVorapaxar


Additional Major Efficacy Outcomes

CV death, MI, Stroke, or Urgent Coronary Revascularization

0%

2%

4%

6%

8%

10%

12%

14%

0 180 360 540 720 900 1080

Even

t Rat

e (%

)


Placebo

Vorapaxar11.2%

12.4%

Hazard Ratio 0.88;95% CI 0.82 to 0.95p = 0.001

CV death or MI

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

0 180 360 540 720 900 1080

Even

t Rat

e (%

)


Placebo

Vorapaxar7.3%

8.2%

Hazard Ratio 0.86;95% CI 0.78 to 0.94p = 0.002


Selected Efficacy Outcomes

CV death, MI, stroke

CV death

MI

Any Stroke

Ischemic stroke

Urgent coronaryrevascularization

CVD, MI, Stroke, UCR, vascular hosp.

All-cause mortality

Placebo(N = 13224)

10.5

3.0

6.1

2.8

2.6

2.6

14.7

5.3


9.3

2.7

5.2

2.8

2.2

2.5

13.1

5.0

HR p-value

0.87

0.89

0.83

0.97

<0.001

0.15

0.001

0.73

0.85

0.88

0.87

0.95

0.059

0.11

<0.001

0.41

3-yr KM rate (%)

UCR = recurrent ischemia leading to urgent coronary revascularization


Efficacy Outcomes No History of Stroke (N= 20,699)

CV death, MI, stroke

CV death

MI

Any Stroke

Ischemic stroke

CVD, MI, Stroke, urgcoronary revasc.

CV death or MI

CVD, MI, Stroke, UCR, vascular hosp.

Placebo(N = 10344)

9.6

2.8

6.4

1.7

1.5

11.8

8.4

14.0


8.3

2.5

5.5

1.5

1.1

10.6

7.4

12.3

HR p-value

0.84

0.87

0.84

0.82

<0.001

0.13

0.004

0.11

0.72

0.86

0.85

0.86

0.013

<0.001

0.002

<0.001

3-yr KM rate (%)

UCR = recurrent ischemia leading to urgent coronary revascularization


CV Death, MI, or Stroke in Major Subgroups

0.5 1 2 5

No 0.85 (0.74, 0.98)Yes 0.88 (0.79, 0.98)

Thienopyridine at Rando 0.76

Stroke 1.03 (0.85, 1.25)PAD 0.94 (0.78, 1.14)MI 0.80 (0.72, 0.89)

Qualifying Athero 0.058<60kg 1.22 (0.88, 1.69)>=60kg 0.85 (0.78, 0.92)

Body weight 0.033>=75 0.91 (0.75, 1.10)<75 0.86 (0.78, 0.94)

Age 0.54Overall 0.87 (0.80, 0.94)

Vorapaxar Better Vorapaxar Worse

Hazard Ratio (95% CI)Subgroup total no.

Yes 0.95 (0.80, 1.11)No 0.84 (0.76, 0.93)

History of Stroke 0.22

26449

234293020

CV Death, MI, or Stroke

185224546

48833787

17779

574620699

1000716442

Interaction p-value

No interaction by sex, or region.


Bleeding EndpointsOverall Population

GUSTO Moderate or Severe

TIMI Clinically Significant

TIMI Non-CABGMajor

Intracranial

Fatal

Placebo(N = 13166)

2.5

11.1

1.8

0.5

0.2


4.2

15.8

2.8

1.0

0.3

HR p-value

1.66

1.46

1.46

1.94

1.46

<0.001

<0.001

<0.001

<0.001

0.19

3-yr KM rate (%)

No significant heterogeneity in GUSTO Mod/Sevbleeding across any of major subgroups


Major Bleeding Endpointsby History of Stroke

2.1

0.90.3

1.8

0.4 0.2

4.1

2.4

0.5

2.5

0.6 0.30

1

2

3

4

5

6

7

8

TIMI Non-CABG Major

ICH Fatal TIMI Non-CABG Major

ICH Fatal

PlaceboVorapaxar

ARD 2.0%HR 1.87P<0.001

ARD 1.5%HR 2.55P<0.001

ARD 0.2%HR 1.48P=0.46

ARD 0.2%HR 1.55P=0.049

ARD 0.1%HR 1.44P=0.30

3-yr KM rate (%)

ARD 0.7%HR 1.35P=0.005

Prior Stroken = 5746

No Hx of Stroken = 20699


GUSTO Moderate or Severe Bleeding in Major Subgroups

5.5

2.2

3.7

2.4 2.4

4.5

2.1

8.4

3.7

7.7

4.0 4.2

7.4

3.4

0123456789

10Placebo Vorapaxar

ARDHR

2.9%1.69

3-yr KM rate (%)

Age ≥75 y Age <75 y Wt <60kg Wt ≥60kg Stroke PAD MI

Age Weight Qual Athero

1.5%1.65

4.0%1.95

1.6%1.64

1.8%1.93

2.9%1.62

1.3%1.61

P-interact 0.87 0.50 0.69


Net Clinical Outcome

1 1.250.90.8Vorapaxar Better Vorapaxar Worse

HR VORA PLAC RRR (%)

0.7

Death, MI, stroke, GUSTO severe bleed

11.9 12.8 8P =0.020

CV death, MI, stroke, UCR,GUSTO mod/sev bleed

13.4 14.0 4P =0.20

All pts


10.0 11.7 16P <0.001


12.0 13.4 12P =0.004No Hx

Stroke/TIAWgt ≥60kg

n = 18,966



10.8 11.8 11P =0.010


12.8 13.4 6P =0.16No Hx

Stroken = 20,699

SummaryWhen added to standard of care, including aspirin & thienopyridine, in stable pts w/ hxatherothrombosis, vorapaxar significantly …• ↓ CV death, MI, or stroke• ↑ mod & severe bleeding, including ICH

In addition, our findings indicate … • significant ↓ in thrombosis adding to standard

rx, including ASA, for long-term rx in pts with prior MI

• unacceptable ICH risk in pts with prior stroke• uncertain benefit in pts with PAD


Conclusions1. PAR-1 antagonism is an effective

approach to reducing recurrent atherothrombosis

2. More intensive antiplatelet therapy for long-term 2° prevention reduces recurrent thrombosis in patients with prior MI

3. Patient selection is necessary to balance the antithrombotic benefit vs. risk of bleeding


For Every 1000 Pts Treated with Vorapaxar

-19

-11

-6 -5

02

10

-25

-20

-15

-10

-5

0

5

10

15

Even

ts /

1000

Pts

No History of Stroke/TIA; Wgt ≥60 kg (n = 18,966)

CVD, MIor StrokeP<0.001

MIP<0.001

CV DeathP=0.033

StrokeP<0.001

Fatal BleedP=NS

ICHP=0.15

*GUSTO Mod/SevP<0.001

*excluding ICH


thrombin receptor antagonist in - intranet da sbcintranet.cardiol.br/coberturaonline/slides/tra...

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