ACS: Antiplatelet, Anticoagulant Therapy and Combinations...

ACS: Antiplatelet, Anticoagulant Therapy and Combinations

The Challenge of a High Benefit/Bleeding Ratio

Deepak L. Bhatt, MD, MPH

Executive Director of Interventional Cardiovascular Programs, BWH Heart and Vascular Center Professor of Medicine, Harvard Medical School

Disclosures for Dr. Bhatt Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology,

Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of

Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight

Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard

Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria:

American College of Cardiology (Senior Associate Editor, Clinical Trials and News,

ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical

Research Institute (clinical trial steering committees), Harvard Clinical Research Institute

(clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive

Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor),

Population Health Research Institute (clinical trial steering committee), Slack Publications

(Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient

Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology

(Deputy Editor); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai,

Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The

Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion

to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, St. Jude Medical; Trustee:

American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda.

This presentation discusses off-label and/or investigational uses of various drugs

and devices.

ACS and Oral Antithrombotic Therapy

THROMBUS

Antiplatelet Agents

Anticoagulants

Fibrin

Factor Xa

Fondaparinux

LMWH

UFH

TF + FVIIa Prothrombin

Fibrinogen

ATIII

Rivaroxaban

Apixaban

Edoxaban

Bivalirudin

Dabigatran

Adapted from Curzen N, Gurbel PA, Myat A, Bhatt DL,

Redwood SR. Lancet 2013; 382: 633–43.

Thrombin

ACS & Plaque Rupture

Fibrin

Factor Xa

Fondaparinux

LMWH

UFH


Fibrinogen

ATIII

Rivaroxaban

Apixaban

Edoxaban

Bivalirudin

Dabigatran



Thrombin

Vorapaxar


Platelet

Fibrin

Factor Xa

Fondaparinux

LMWH

UFH


Fibrinogen

ATIII

Rivaroxaban

Apixaban

Edoxaban

Bivalirudin

Dabigatran



Granule

Secretion

Amplification

P2Y

12

ADP

Thrombin

Vorapaxar

Clopidogrel

Prasugrel

Ticagrelor

Cangrelor

Aspirin

TxA2

Collagen/vWF


Platelet

+

GPIIb/IIIa Activation

Platelet Aggregation

Abciximab

Eptifibatide

Tirofiban

Ischemic Events

Platelet-Fibrin Clot

TRITON TIMI-38: Net Clinical Benefit

Bleeding Risk Subgroups

OVERALL

>= 60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior

Stroke / TIA

Age

Wgt

Risk (%)

+ 54

-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel Better HR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post hoc analysis

Wiviott SD et al. NEJM. 2007;357:2001-15.

Bhatt DL. N Engl J Med 2007;357:2078-81.

Major Bleeding

Transfusion Hypotension Cessation of DAPT

Mortality

Bhatt DL. In Braunwald: Heart Disease Online 2005.

Potential Relationship Between Bleeding

and Mortality

Ischemia Stent Thrombosis Inflammation

Population RR (95% CI) p value

Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046

(n=12,153)

Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20

(n=3,284)

Overall Population† 0.93 (0.83, 1.05) 0.22 (n=15,603)

Primary Efficacy Results (MI/Stroke/CV

Death) by Pre-Specified Entry Category

0.6 0.8 1.4 1.2

Clopidogrel + ASA

Better

Placebo + ASA

Better

1.6 0.4

* A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-

specified subgroups of patients † 166 patients did not meet any of the main inclusion criteria

Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

10

8

6

4

2

0

CHARISMA―Prior MI

0 6 12 18 24 30

HR=0.774 (95% CI [0.613–0.978])

P=0.031

N=3,846

Pri

mary

Ou

tco

me E

ven

t R

ate

(%

)

Months Since Randomization

8.3%

6.6%

Placebo + ASA

Clopidogrel + ASA

Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

Timing of Severe or Moderate Bleeding

Placebo + ASA

Clopidogrel + ASA

Days Since Randomization

15 60 135 270 450 630 810

0.00008

0.00007

0.00006

0.00005

0.00004

0.00003

0.00002

0.00001

0

Hazard

Fu

ncti

on

/d


PEGASUS – TIMI 54

Stable pts with history of MI 1-3 yrs prior

+ 1 additional atherothrombosis risk factor* N ~ 21,000

Ticagrelor

90 mg bid

Placebo

RANDOMIZE

DOUBLE BLIND

Follow-up Visits

Q4 mos for 1st yr, then Q6 mos

Planned treatment with ASA 75 – 150 mg &

Standard background care

Primary Efficacy Endpoint: CV Death, MI, or Stroke

Primary Safety Endpoint: TIMI Major Bleeding

* Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD,

or chronic non-end stage renal dysfunction

Min 12 mos and median 26 mos follow-up

Event-driven trial

Ticagrelor

60 mg bid

Bonaca MP, Bhatt DL, Braunwald E, et al. Am Heart J. 2014;167:437-44.

PEGASUS – TIMI 54

Bonaca MP, Bhatt DL, Cohen M, et al. NEJM. 2015.

PEGASUS TIMI 54 – Components of Primary Endpoint


PEGASUS – TIMI 54


doi: 10.1093/eurheartj/ehv443

CHARISMA 125 1903 162 1943 PRODIGY 63 732 69 733 ARCTIC-Int’n 3 156 4 167 DAPT 59 1805 108 1771 DES-LATE 56 1512 66 1551 PEGASUS 980 14095 578 7067

TOTAL 1286 20203 987 13232

6.4% 7.5%

Primary Endpoint – CV Death, MI, or Stroke

P = 0.001

0.77 (0.61 - 0.98) 0.91 (0.65 - 1.28) 0.79 (0.18 - 3.51) 0.52 (0.38 - 0.72) 0.85 (0.60 - 1.21) 0.84 (0.76 - 0.94)

Study Events Total Events Total

Extended Aspirin Risk Ratio

DAPT Alone (95% CI)

0.2 0.5 1 2 Extended DAPT Better Aspirin Alone Better

0.78 (0.67 - 0.90)

Udell JA, Bonaca MP, Collet JP, et al. Eur Heart J 2015.


TOTAL 472 20203 344 13232

2.3% 2.6%

P = 0.03

0.82 (0.57 - 1.18) 1.00 (0.61 - 1.64) 0.36 (0.01 - 8.69) 0.67 (0.31 - 1.44) 1.00 (0.55 - 1.83) 0.85 (0.71 - 1.00)



DAPT Alone (95% CI)

0.2 0.5 1 2 Extended DAPT Better Aspirin Alone Better

0.85 (0.74 - 0.98)

Cardiovascular Death


Individual CV Endpoints

6.4

2.3

3.5

1.4

0.6

7.5

2.6

4.4

1.7 1.4

0

1

2

3

4

5

6

7

8

9

10

MACE CV Death MI Stroke StentThrombosis(Def/Prob)

Eve

nt

Ra

te (

%)

Extended DAPT

Aspirin Alone

RR 0.78

P = 0.001

RR 0.85

P = 0.03

RR 0.70

P = 0.003

RR 0.81

P = 0.02 RR 0.50

P = 0.02



TOTAL 371 20054 144 13161

1.9% 1.1%

P = 0.004

1.17 (0.76 - 1.79) 1.50 (0.53 - 4.20) 5.35 (0.26 - 110.6) 2.38 (1.27 - 4.43) 1.27 (0.79 - 2.03) 2.50 (1.86 - 3.36)



DAPT Alone (95% CI)

0.5 1 2 5 Extended DAPT Better Aspirin Alone Better

1.73 (1.19 - 2.50)

Major Bleeding


Subgroup Analysis: Primary Endpoint

Event Rate (%)

Hazard Ratio

0.73

0.88

0.68

NE

0.82

Prasugrel

Clopidogrel DAPT

Regimen

STEMI

NSTEMI

UA Index

ACS

0.88

0.83

≥ 75 years

< 75 years Age

0.84

0.84 Female

Male Sex

0.78 (0.67 - 0.90) Overall

Aspirin Alone

NE

6.9

7.1

8.2

4.6

12.9

6.8

7.7

7.7

7.5

Extended DAPT

5.8

NE

5.6

7.6

3.3

11.1

5.9

6.9

6.6

6.4

0.2 0.5 1 2

Extended DAPT Better Aspirin Alone Better All P-interactions >0.05 Abbreviations: NE: no estimate

Ticagrelor 7.0 8.2 0.84

0.87

0.76

≥ 24 months

< 24 months Time from

Index MI 6.7

6.1

7.4

7.3

0.83

0.78

No

Yes History of

PCI 9.9

5.7

11.3

6.7

EXAMINATION:

EES vs BMS in Acute MI

Sabate M, et al. Lancet 2012.

First generation drug eluting stents Second generation drug eluting stents

Stent restenosis Stent restenosis Stent thrombosis Stent thrombosis

Death, MI

Death, MI Death, MI

Death, MI Death, MI Death, MI

Bhatt DL. Lancet 2012.

Can 2nd Generation DES Reduce Death?

OPTIMIZE Trial: NACCE at 1 Year (All-Cause Death, MI, Stroke, Major Bleeding)

Month 0 1 3 6 12

No. at risk 1563 1520 1504 1468 1384

No. events 18 25 11 18 21

No. at risk 1556 1514 1497 1466 1381

No. events 16 25 11 16 22

Log-Rank P = 0.84

HR 1.03 (0.77 – 1.38)

Cu

mu

lati

ve

In

cid

en

ce

of

NA

CC

E (

%)

Time After Initial Procedure (Months)

0 12

0

10

15

5

3 6 9

6.0 5.8

12M DAPT

3M DAPT

Non-inferiority

P-value = 0.002

Feres F. et al, JAMA. 2013.

Optimal Duration of DAPT?

Eisen A, Bhatt DL. Nature Reviews Cardiology. 2015.

ACCOAST Design

Prasugrel 30 mg

Prasugrel 60 mg Prasugrel 30 mg

Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days

PCI

1° Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days

Placebo

Coronary

Angiography

n~4100 (event driven)

Coronary

Angiography

PCI

CABG

or

Medical

Management

(no prasugrel)

CABG

or

Medical

Management

(no more prasugrel)

Montalescot G et al. Am Heart J 2011;161:650-656

Randomize 1:1 Double-blind

NSTEMI + Troponin ≥ 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

5

10

15

1996

2037

1788

1821

1775

1809

1769

1802

1762

1797

1752

1791

CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout

1621

1616

No. at Risk, Primary

Efficacy End Point:

No pre-treatment

Pre-treatment

Pre-treatment 10.8 10.0

Pre-treatment

Hazard Ratio, 0.997 (95% 0.83, 1.20) P=0.98 P=0.81

(95% 0.84, 1.25) Hazard Ratio, 1.02

No Pre-treatment 10.8

9.8 No Pre-treatment

1° Efficacy End Point @ 7 + 30 days

Montalescot G et al. NEJM 2013

All TIMI (CABG or non-CABG) Major Bleeding

Days From First Dose

0 5 10 15 20 25 30

En

dp

oin

t (%

)

0

1

2

3

4

5

All TIMI Major Bleeding

Pre-treatment 2.9

Pre-treatment 2.6



1996 2037

1947 1972

1328 1339

1297 1310

1288 1299

1284 1297

1263 1280

No. at Risk, All TIMI Major Bleeding: No pre-treatment Pre-treatment

Hazard Ratio, 1.97 (95% 1.26, 3.08) P=0.002

Hazard Ratio, 1.90 (95% 1.19, 3.02) P=0.006

Montalescot G et al. NEJM 2013

Studies of pretreatment with oral P2Y12 receptor inhibitors in patients with stable CAD and NSTE-ACS

Capodanno D & Angiolillo DJ. Circ Cardiovasc Interv 2015

Studies of pretreatment with oral P2Y12 receptor inhibitors in patients with STEMI undergoing Primary PCI

Capodanno D & Angiolillo DJ. Circ Cardiovasc Interv 2015

Capodanno D & Angiolillo DJ. Circ Cardiovasc Interv 2015 [in press]

Time from hospital admission or first medical contact to coronary angiography in studies of ACS & STEMI

Cangrelor

► Direct platelet P2Y12 receptor antagonist

► ATP analogue MW=800 Daltons

► Parenteral administration

► T1/2 = 3 to 6 minutes

► Offset = 60 minutes

N N

N N

N H

S C F

3

O H O H

O

O P

O

O

P P

O O

O Cl

Cl

O O

O

S

4Na +

Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the

platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of

platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55.

CHAMPION PHOENIX Study Design

1 2 to 4 hours 0

Cangrelor2 bolus & infusion (30ug/kg; 4ug/kg/min) Clopidogrel

600 mg oral CHAMPION PHOENIX

N = 10,900 MITT

SA/ NSTE-ACS/ STEMI

Patients requiring PCI1

P2Y12 inhibitor naïve

OR Placebo3 oral (right before PCI or right after, per physician)

Placebo2 bolus & infusion Placebo oral

PCI ~30’

OR Clopidogrel3 (600 mg or 300 mg oral, per physician)

1Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis.

Double blind study medication was administered as soon as possible following randomization. 2Study drug Infusion (cangrelor or matching placebo) was continued for 2-4 hours at the discretion of the treating physician. At the end of the infusion

patients received a loading dose of clopidogrel or matching placebo and were transitioned to maintenance clopidogrel therapy. 3Clopidogrel loading dose (or matching placebo) was administered as directed by the investigator. At the time of patient randomization, a clopidogrel loading

dose of 600 mg or 300 mg was specified by the investigator.

MITT=modified intent-to-treat; NSTE-ACS=non-ST-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina;

STEMI=ST-elevation MI.

Rand

Death/ MI/ IDR/ Stent Thrombosis within 48 Hours

Patient at Risk Hours from Randomization

Cangrelor: 5472 5233 5229 5225 5223 5221 5220 5217 5213

Clopidogrel: 5470 5162 5159 5155 5152 5151 5151 5147 5147

cangrelor

clopidogrel 5.9%

4.7%

Log Rank P Value = 0.006

Event R

ate

(%

)

Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013.

cangrelor

clopidogrel

Log Rank P Value = 0.01

Patient at Risk Hours from Randomization

Cangrelor: 5472 5426 5421 5419 5419 5418 5417 5416 5414

Clopidogrel: 5470 5392 5389 5388 5386 5385 5385 5383 5383

1.4%

0.8%

Event R

ate

(%

)

Stent Thrombosis within 48 Hours

Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013.

Non-CABG Bleeding at 48 Hours, Safety

Bleeding Scale Cangrelor

(N=5529)

Clopidogrel

(N=5527) OR (95% CI) P Value

GUSTO Severe 9 (0.16%) 6 (0.11%) 1.50 (0.53,4.22) 0.44

GUSTO Moderate 22 (0.4%) 13 (0.2%) 1.69 (0.85,3.37) 0.13

GUSTO Severe +

Moderate 31 (0.6%) 19 (0.3%) 1.63 (0.92,2.90) 0.09

TIMI Major 5 (0.1%) 5 (0.1%) 1.00 (0.29,3.45) >0.999

TIMI Minor 9 (0.2%) 3 (0.1%) 3.00 (0.81,11.10) 0.08

TIMI Major + Minor 14 (0.3%) 8 (0.1%) 1.75 (0.73,4.18) 0.2

Any Blood Transfusion 25 (0.5%) 16 (0.3%) 1.56 (0.83,2.93) 0.16

ACUITY Major 235 (4.3%) 139 (2.5%) 1.72 (1.39,2.13) <0.001

ACUITY w/out hematoma 42 (0.8%) 26 (0.5%) 1.62 (0.99,2.64) 0.05

Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013 at www.nejm.org

Removal of IPST and all MIs

solely identified by biomarkers

Death/MI with Symptom or

ECG/IDR/ARC-ST

1.6%

(86/5470)

2.4%

(130/5469) 0.66 (0.50, 0.86)

Removal of IPST and MIs solely identified

by CK-MB >3xULN but <10xULN

Death/MI≥10xULN or

Symptoms or ECG/IDR/ARC-ST

1.9%

(106/5470)

2.9%

(161/5469) 0.65 (0.51, 0.83)

Sensitivity Analyses

Removal of IPST

Death/MI/IDR/ARC-ST 4.2%

(230/5470)

5.2%

(286/5469) 0.80 (0.67, 0.95)

Cangrelor

(N=5472)

Clopidogrel

(N=5470)

Odds Ratio

(95% CI)

Protocol-defined primary endpoint 4.7%

(257/5470)

5.9%

(322/5469) 0.79 (0.67, 0.93)

Death/MI/IDR/ST

0.1 1.0 10.0

Results: Sensitivity analyses for composite endpoints

Favors Cangrelor Favors Clopidogrel

Alexopolous D, Bhatt DL, Hamm CW, Steg PG, Stone GW. Am Heart J 2015;170:3-12

CHAMPION PHOENIX Overall and STEMI outcomes, 48 h

Primary Endpoint Cangrelor Clopidogrel OR

Overall mITT (N=10,942) 257/5470 (4.7%) 322/5469 (5.9%) 0.78 (0.66-0.93)

STEMI (n=1,991) 27/961 (2.8%) 38/1030 (3.7%) 0.75 (0.46-1.25)

Stent Thrombosis

Overall mITT (N=10,942) 46/5470 (0.8%) 74/5469 (1.4%) 0.62 (0.43-0.90)

STEMI (n=1,991) 12/961 (1.2%) 20/1030 (1.9%) 0.64 (0.31-1.31)

Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013;68:1303-13 and online appendix.

GUSTO sev/mod bleeding

Overall safety (N=11,056) 31/5529 (0.6%) 19/5527 (0.3%) 1.63 (0.92-2.90)

STEMI (n=2,070) 12/1000 (1.2%) 7/1070 (0.7%) 1.84 (0.72-4.70)

0.1 1 10

0.1 1 10

0.1 1 10

Oral Pretreatment in STEMI

Courtesy of Ghobrial J, Gibson CM, Pinto DS.


Courtesy of Ghobrial J, Gibson CM, Pinto DS.

Bhatt DL, Hulot J-S, Moliterno, DJ, Harrington RA. Circ Res 2014; 114:1929-1943.

In Fuster V, Kovacic J. Compendium on ACS.

ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

RE-LY

Combined

Favors NOAC Favors Warfarin

0.88 (0.75 - 1.02)

0.80 (0.67 - 0.95)

0.88 (0.75 - 1.03)

0.66 (0.53 - 0.82)

0.81 (0.73 - 0.91)

Risk Ratio (95% CI)

p=<0.0001

0.5 1 2

All NOACS: Stroke or SEE

[Random Effects Model]

N=58,541

Heterogeneity p=0.13

[60 mg]

[150 mg]

Ruff CT, et al. Lancet 2014;383:955-962

All-Cause Mortality

MI

Hemorrhagic Stroke

Ischemic Stroke

0.90 (0.85 - 0.95)

0.97 (0.78 - 1.20)

0.49 (0.38 - 0.64)

0.92 (0.83 - 1.02)

Risk Ratio (95% CI)

p=0.0003

p=0.77

p<0.0001

p=0.10


0.2 0.5 1 2

Secondary Efficacy Outcomes

Heterogeneity p=NS for all outcomes


ARISTOTLE

ROCKET AF

Combined


Risk Ratio (95% CI)

0.80 (0.71 - 0.90)

0.71 (0.61 - 0.81)

1.03 (0.90 - 1.18)

0.94 (0.82 - 1.07)

0.86 (0.73 - 1.00)

0.5 1 2

All NOACS: Major Bleeding

[Random Effects Model]

N=58,498 p=0.06

Heterogeneity p=0.001

RE-LY [150 mg]

ENGAGE AF-TIMI 48 [60 mg]


GI Bleeding

ICH

1.25 (1.01 - 1.55)

0.48 (0.39 - 0.59)

Risk Ratio (95% CI)

p=0.043

p<0.0001


0.2 0.5 1 2

Secondary Safety Outcomes

Heterogeneity

ICH, p=0.22

GI Bleeding, p=0.009


When is a Double Better Than a Triple?

Bhatt DL. JACC 2015.

Rivaroxaban Use in Patients With AF Undergoing PCI: PIONEER AF-PCI

• Primary endpoint: TIMI major, minor, and bleeding requiring medical attention

• Secondary endpoint: CV death, MI, stroke, and stent thrombosis

Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min.

†Alternative P2Y12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor.

‡Low-dose aspirin (75-100 mg/d).

2100

patients

with NVAF

No prior

stroke/TIA

PCI with

stent

placement

R

A

N

D

O

M

I

Z

E

1,6, or 12 months

Rivaroxaban15 mg qd*

Clopidogrel 75 mg qd†

Rivaroxaban 15mg qd

Aspirin 75-100 mg qd

Rivaroxaban 2.5 mg bid


Aspirin 75-100 mg qd‡

VKA (target INR 2.0-3.0)


VKA (target INR 2.0-3.0)



≤72

hours

After

Sheath

removal

1,6, or 12 months

End of treatment at 12 months

1° End Point

Thrombotic

Event Rate

(Death + MI + Stroke/SE)

Plus

Clinically Relevant Bleeding Rate

(ISTH Major)

Screening

Dabigatran 110mg BID + P2Y12 inhibitor

12M

Warfarin (INR 2.0-3.0) + P2Y12 inhibitor + ASA

6M

Dabigatran 150mg BID + P2Y12 inhibitor

3M 9M 15M 18/24/30M

or EOT

Worldwide Event Driven Trial

R

Paroxysmal, persistent or permanent NVAF

(PCI with stenting [BMS or DES] elective or ACS)

Warfarin Apixaban

Primary outcome: major/clinically relevant bleeding (through 6 months)

Secondary objective: Death, MI, stroke, stent thrombosis

Randomize

n =4,600

Patients

Inclusion

AF (prior, persistent, and/or >6

hours duration)

CHADS ≥ 1

Physician decision that oral

anticoag is indicated

ACS or PCI with planned

P2Y12 inhibitor for 6 months

Exclusion

• Contraindication to DAPT

• Other reason for warfarin

(prosthetic valve,

moderate/severe MS)

Apixaban Versus Warfarin in Patients with

AF and ACS or PCI: The AUGUSTUS Trial

ASA placebo ASA placebo

P2Y12 inhibitor for all patients x 6 months

Aspirin for all on the day of ACS or PCI

Aspirin versus placebo after randomization

COMPASS

Conclusions

• Dual antiplatelet therapy indicated for at least 1 year after ACS

• Likely benefit > 1 year in patients w/ prior MI – CHARISMA subgroup

• PEGASUS showed a significant reduction in CV death/MI/stroke

• PEGASUS also showed an increase in non-fatal bleeding

• Duration for elective 2nd generation DES likely shorter, for ACS longer

• Cangrelor may be an option in patients not pretreated

• Unclear what to do with afib + ACS +/- PCI

• Important to individualize therapy based on ischemic/bleeding risks

www.brighamandwomens.org/heart

Deepak L. Bhatt, MD, MPH Executive Director of Interventional Cardiovascular Programs, BWH Heart & Vascular Center Professor of Medicine, Harvard Medical School 1 (857) 307-1992 [email protected]

Thank You!

Atherothrombosis:

Clinical Manifestations

Stroke TIA Intracranial stenosis

Carotid artery stenosis CEA Carotid stenting

Renal artery stenosis Renal artery stenting

Peripheral arterial disease Acute limb ischemia Claudication Amputation Endovascular stenting Peripheral bypass Abnormal ABI

Acute coronary

syndromes

– STEMI

– NSTEMI

– Unstable angina

Stable CAD

Atrial Fibrillation

Angioplasty

Bare metal stent

Drug eluting stent

CABG

Abdominal aortic

aneurysm (AAA)

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

OR and Attributable Risk for Baseline Factors Associated with Seath by 12 Months

Pe

rcen

tage a

ttrib

uta

ble

fra

ction

20

Myocardial infarction

definitions and late mortality

> 1 x ULN

A

15

10

5

0

20

15

10

5

1

> 2 x ULN > 3 x ULN > 5 x ULN > 10 x ULN

Percentage attributable fraction

Odds Ratio

Od

ds R

atio

2.0

2.8 3.5

5.3

7.6

11.6%

13.2% 13.4% 13.7%

4.6%

B

20

15

10

05

0

Pe

rcen

tage a

ttrib

uta

ble

fra

ction

20

15

10

5

1

Bleeding definitions and late mortality

Od

ds R

atio

Protocol major/

minor bleed

Protocol major

bleed

TIMI major/

minor bleed

TIMI

major bleed

1.6 2.2

4.0%

3.9%

2.3

3.5%

6.1

12.0%

Chew DP, Bhatt DL, Lincoff AM, et al. Heart 2006;92:945–50. From the REPLACE-2 database.

Odds ratio is represented by dotted lines; attributable risk by shaded area

PCI CABG SIHD NSTE-ACS STEMI

6

month

1

year

DAPT

(Cl, Ti)

up to 12

m (I; B)

Med

Rx

PCI

(BMS

or

DES)

No

Reper

fusion

Lytic BMS DES

DAPT

(Cl, Pr)

at least

12 m

DAPT

(Cl) at

least

14 d

and up

to 1

year

(I;C)

No

Rec

DAPT

(Cl, Pr)

at least

30 d

and up

to 1

year

DAPT

Beyond

12 m

(IIb; C)

(IIa;B

for Pr);

(I;C for

Cl; (IIa;B

for Prl;

(I;C for

Cl;

BMS/

No

ACS

DAPT

(Cl) at

least 1

m and

ideally

up to 1

year

(I;B)

DES/

No

ACS

DAPT

(Cl) at

least

12

months

(I;B)

BMS or

DES

for

ACS

DAPT (Cl.Pr,Ti)

at least

12

months

(I;B)

DAPT Beyond

12

months

for DES

(IIb;C)

DAPT Beyond

12

months

for DES

(IIb;C)

No

Rec

Cl=clopidogrel; Pr=prasugrel; Ti=ticagrelor Cl=clopidogrel; Ti=ticagrelor; Pr=prasugrel

DAPT

(Cl) in

certain

high-

risk patients

(IIb;B)

Green=class I rec; Yellow=class IIa rec; Orange=class IIb rec

DAPT

(Cl, Pr,

Ti)

at least

12 m

(I; B)

Courtesy of Dr. Glenn Levine

Primary Endpoint (MI/Stroke/CV Death) in

Patients With Previous MI, IS, or PAD* “CAPRIE-like Cohort”

RRR: 17.1 % (95% CI: 4.4%, 28.1%)

P=0.01

Pri

mary

Ou

tco

me E

ven

t R

ate

(%

)

0

2

4

6

8

10


0 6 12 18 24 30

Clopidogrel + ASA

Placebo + ASA

N=9,478

* Post hoc analysis.


8.8%

7.3%

CHARISMA―CAD Without Prior MI

10

8

6

4

2

0

0 6 12 18 24 30

HR=1.103 (95% CI (0.770–1.580])

P=0.593

N=1,989

Pri

mary

Ou

tco

me E

ven

t R

ate

(%

)


6.3%

5.7%

Placebo + ASA

Clopidogrel + ASA


PEGASUS TIMI 54 – Other Efficacy Outcomes


THEMIS

Primary endpoint : Composite of CV death, MI or stroke

Secondary endpoint: Composite of all-cause death, MI or stroke; CV death; All-cause death

Primary safety: TIMI Major bleeding

Event driven study; 750 CV events required. 2 years mean follow-up. (n=19 000)

* At high risk of CV events defined as history of PCI or CABG or angiographic evidence of ≥ 50% lumen stenosis of at least 1 coronary artery

Ticagrelor Placebo

Type 2 diabetes; men and women ≥ 50 years ≥ 6 months glucose lowering drug treatment

At high risk for CV events*

No previous MI or stroke

No planned use of ADP receptor antagonist or planned revascularisation

Low-dose ASA background therapy based on individual risk

Design and main eligibility criteria

http://www.clinicaltrials.gov/show/NCT01991795

Median Time of Late Stent Thrombosis

p = 0.04 p = 0.0003 p = 0.0052

Months

Bavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM 2006.

0

4

8

12

16

20

DES/BMS SES/BMS PES/BMS

1.9

0.4 0.1

1.7

4.0

1.1

0.3 0.2

1.6

4.2

0

1

2

3

4

5

6

7

8

9

10

MajorBleeding

ICH FatalBleeding

Non-CVDeath

All-CauseDeath

Eve

nt

Ra

te (

%)

Extended DAPT

Aspirin Alone

RR 1.73

P = 0.004

P = NS

RR 1.05

P = NS

RR 0.92

P = NS

Major Bleeding Events and Safety

P = NS


Any Stent Thrombosis: Probability Best

SES, 0.12

PES, 0

EES, 86.32

ZES, 0.98

ZES-R, 12.59BMS, 0.01

% Probability of Lowest Any ST Rate

Bangalore et al. Circulation. 2012;125:2873-2891.

66 66

DAPT: Design

66

50% of patients continue on

Dual Antiplatelet Therapy

18 mos. 12 mos.

50% of patients receive

aspirin + placebo

Total 33 month patient evaluation including additional 3-month follow-up

All patients on

aspirin +open-label

thienopyridine

therapy for

12 months

DES n =

23,210

BMS n =

2,985

Completed

Enrollment

2011

1:1 Randomization

at month 12

www.daptstudy.org www.clinicaltrials.gov – NCT00977938 Mauri L et al. Am Heart J. 2010;160:1035-41.

http://www.daptstudy.org/

http://www.clinicaltrials.gov/

ST 12-30 Months: HR 0.29 (0.17-0.48) 0.4% vs. 1.4% P<0.001

Thienopyridine

Placebo

10%

8%

6%

4%

2%

0%

Cu

mu

lati

ve In

cid

en

ce o

f S

ten

t

Th

rom

bo

sis

an

d M

AC

CE

12 15 18 21 24

Months After Enrollment

27 30

Study Drug

33

# At Risk Treatment Ends Thienopyridine 5020 4934 4870 4828 4765 4686 4642 3110

Placebo 4941 4845 4775 4721 4651 4603 4556 3105

CVD/MI/Stroke 12-30 Months: HR 0.71 (0.59-0.85) 4.3% vs. 5.9% P<0.001

Mauri L, et al. NEJM 2014


Co-Primary Effectiveness End Points &

Components: 12-30 Months

69

0.4% 0.3% 0.1%

4.3%

2.0% 2.1%

0.5% 0.3%

1.4% 1.2%

0.1%

5.9%

1.5%

4.1%

0.7%

0.2%

0%

1%

2%

3%

4%

5%

6%

Cu

mu

lati

ve In

cid

en

ce (

%)

Thienopyridine (N=5020) Placebo (N=4941)

<0.001 <0.001

0.55

<0.001

0.052

<0.001

0.16

<0.001

0.68


MACCE

Moderate/Severe

Bleeding

Stent Thrombosis

Interaction P=0.69 Interaction P=0.03 Interaction P=0.21

Treatment Effect According to ACS Status

at 12-30 Months: Primary Endpoints All Randomized Subjects (N=11648)

P<0.001 P<0.001

P<0.001 P=0.08

P=0.005 P=0.007

70

Yeh R, et al. JACC 2015

BARC 2, 3, or 5 Bleeding

BARC 5 Bleeding

(Fatal Bleeding)

Death

Interaction P=0.13 Interaction P=0.67 Interaction P=0.55

Treatment Effect According to ACS Status

at 12-30 Months – Secondary Endpoints All Randomized Subjects (N=11648)

P=0.61 P=0.04

P<0.001 P<0.001

P=0.97 P=0.42

71

Yeh R, et al. JACC 2015

3 months

6 months

24 months

EXCELLENT

DAPT

ITALIC

ISAR SAFE

12 months

48 months

30 months

ARCTIC

Capodanno D, Angiolillo DJ. Circulation. 2013.

Trials of DAPT Duration

Ongoing trials in green

Mortality with Extended Duration DAPT After

DES: A Pairwise and Bayesian Network

Meta-Analysis of 10 RCTs and 31,666 Pts

25% ↓

MI

with

prolonged

DAPT

(p=0.01)

MI HR

(95% CI)

ARTIC Interruption

DAPT

DES LATE

EXCELLENT

ISAR SAFE

ITALIC

OPTIMIZE

PRODIGY

RESET

SECURITY

I-V (I2=29.3%, p=0.17); p value for ES<0.0001

Longer DAPT better

D+L: p value for ES=0.01

Weight

(%)

Events

Group 1

Events

Group 2

1.04 (0.41, 2.62)

1.94 (1.55, 2.44)

1.43 (0.80, 2.58)

1.86 (0.74, 4.67)

0.93 (0.44, 1.97)

1.50 (0.42, 5.32)

1.17 (0.77, 1.76)

1.04 (0.60, 1.79)

0.50 (0.91, 2.72)

1.06 (0.53, 2.16)

1.51 (1.28, 1.77)

1.34 (1.07, 1.69)

Study

3.01

50.33

7.56

3.05

4.61

1.61

15.16

8.67

0.75

5.25

100.00

9/624

198/4941

27/2514

13/722

13/1997

6/912

49/1563

26/751

2/1059

16/682

359/

15765

9/635

99/5020

19/2531

7/721

14/2003

4/910

42/1556

25/750

1/1058

15/717

238/15901

Shorter DAPT better

2 .1 3 5 1 .5

Palmerini T, ….Stone GW. Lancet 2015:on-line

ES=effect size




41% ↓

stent

thrombosis

with

prolonged

DAPT

(p=0.06)

Definite/

Probable ST HR

(95% CI)

DAPT

EXCELLENT

ISAR SAFE

ITALIC

OPTIMIZE

PRODIGY

RESET

SECURITY


2 .1 3

Shorter DAPT better

5 1 .5

Longer DAPT better


Weight

(%)

Events

Group 1

Events

Group 2

2.98 (1.95, 4.58)

6.02 (0.72, 49.96)

1.25 (0.33, 4.65)

7.38 (0.76, 71.00)

1.08 (0.49, 2.36)

1.24 (0.49, 3.14)

0.66 (0.11, 3.98)

0.67 (0.11, 3.86)

2.04 (1.48, 2.80)

Study

55.53

2.25

5.79

1.97

16.38

11.73

3.14

3.20

100.00

65/4941

6/722

5/1997

3/912

13/1563

10/751

2/1059

2/682

106/

13251

19/5020

1/721

4/2003

0/910

12/1556

8/750

3/1058

3/717

53/

13370 1.68 (0.98, 2.87)

ES=effect size





8% ↑

cardiac

mortality

with

prolonged

DAPT

(p=NS)

Cardiac Death HR

(95% CI)

DAPT

DES LATE

EXCELLENT

ITALIC

OPTIMIZE

PRODIGY

RESET

SECURITY

I-V (I2=0.0%, p=0.85); p value for ES=0.52

2 .1 3

Shorter DAPT better

5 1 .5

Longer DAPT better


Weight

(%)

Events

Group 1

Events

Group 2

1.04 (0.70, 1.53)

0.68 (0.38, 1.23)

0.67 (0.11, 3.99)

1.67 (0.40, 6.97)

0.90 (0.55, 1.49)

0.92 (0.53, 1.58)

0.50 (0.91, 2.73)

1.64 (0.41, 6.59)

0.93 (0.73, 1.17)

0.93 (0.73, 1.17)

Study

35.40

15.69

1.68

2.65

21.79

18.14

1.86

2.81

100.00

100.00

52/4941

19/2514

2/722

5/912

29/1563

25/751

2/1059

5/682

139/

13144

50/5020

28/2531

3/721

3/910

32/1556

27/750

4/1058

3/717

150/13263

ES=effect size





72% ↑

bleeding

with

prolonged

DAPT

(p<0.0001)

Major Bleeding HR

(95% CI)

ARTIC Interruption

DAPT

DES LATE

EXCELLENT

ISAR SAFE

ITALIC

OPTIMIZE

PRODIGY

RESET

SECURITY


2 .1 3 5 1 .5

Longer DAPT better

D+L: p value for ES<0.0001

Weight

(%)

Events

Group 1

Events

Group 2

0.15 (0.02, 1.20)

0.57 (0.43, 0.75)

0.71 (0.42, 1.20)

0.50 (0.09, 2.73)

0.80 (0.21, 2.98)

0.13 (0.01, 1.30)

0.71 (0.32, 1.60)

0.38 (0.14, 1.07)

0.75 (0.17, 3.35)

0.51 (0.16, 1.59)

0.58 (0.47, 0.72)

0.58 (0.47, 0.72)

Study

1.10

59.86

16.81

1.59

2.63

0.78

7.16

4.48

2.08

3.51

100.00

1/624

72/4941

24/2514

2/722

4/1997

0/912

10/1563

5/751

2/1059

4/682

124/

15765

7/635

129/5020

34/2531

4/721

5/2003

3/910

12/1556

6/750

6/1058

8/717

221/15901

Shorter DAPT better

ES=effect size





49% ↑

Non-

cardiac

mortality

with

prolonged

DAPT

(p=0.006)

Non-cardiac Death HR

(95% CI)

DAPT

DES LATE

EXCELLENT

ITALIC

OPTIMIZE

PRODIGY

RESET

SECURITY


2 .1 3

Shorter DAPT better

5 1 .5

Longer DAPT better


Weight

(%)

Events

Group 1

Events

Group 2

0.47 (0.29, 0.76)

0.68 (0.34, 1.37)

0.50 (0.09, 2.74)

0.75 (0.17, 3.30)

1.07 (0.50, 2.28)

0.90 (0.49, 1.65)

0.73 (0.16, 3.26)

0.60 (0.15, 2.42)

0.67 (0.51, 0.89)

0.67 (0.51, 0.89)

Study

34.27

16.38

2.73

3.62

13.82

21.58

3.50

4.11

100.00

100.00

22/4941

13/2514

2/722

3/912

14/1563

20/751

3/1059

3/682

80/

13144

48/5020

19/2531

4/721

4/910

13/1556

22/750

4/1058

5/717

119/13263

ES=effect size





22% ↑

mortality

with

prolonged

DAPT

(p=0.02)

All-cause Death HR

(95% CI)

ARTIC Interruption

DAPT

DES LATE

EXCELLENT

ISAR SAFE

ITALIC

OPTIMIZE

PRODIGY

RESET

SECURITY


2 .1 3 5 1 .5

Longer DAPT better


Weight

(%)

Events

Group 1

Events

Group 2

1.32 (0.49, 3.55)

0.75 (0.56, 1.02)

0.71 (0.45, 1.10)

0.57 (0.17, 1.95)

0.66 (0.27, 1.63)

1.14 (0.41, 3.15)

0.95 (0.63, 1.45)

0.91 (0.61, 1.37)

0.62 (0.20, 1.88)

1.00 (0.37, 2.66)

0.82 (0.69, 0.98)

0.82 (0.69, 0.98)

Study

3.03

33.00

14.85

1.99

3.67

2.85

17.07

18.12

2.36

3.05

100.00

100.00

9/624

74/4941

32/2514

4/722

8/1997

8/912

43/1563

45/751

5/1059

8/682

236/

15765

7/635

98/5020

46/251

7/721

12/2003

7/910

45/1556

49/750

8/1058

8/717

287/1590

Shorter DAPT better

ES=effect size


2012 ACCF/AHA Focused Update

Unstable Angina/NonSTEMI Guidelines

Class IIb Recommendations

Jneid H et al. J Am Coll Cardiol. 2012;60:645-81.

1. Platelet function testing to determine platelet inhibitory response in

patients with UA/NSTEMI (or, after ACS and PCI) on P2Y12 receptor

inhibitor therapy may be considered if results of testing may alter

management. (Level of Evidence: B)

2. Genotyping for a CYP2C19 loss of function variant in patients with

UA/NSTEMI (or, after ACS and with PCI) on P2Y12 receptor inhibitor

therapy might be considered if results of testing may alter management.

(Level of Evidence: C)

Nonadherence >> Resistance

Kolandaivelu K, Bhatt DL. Nat Rev Cardiol. 2010;7:461-467.

CHAMPION Trials Study Designs

1 2 hours 0

PCI ~30’

Cangrelor bolus then infusion Clopidogrel 600 mg oral

CHAMPION PHOENIX

n=10,942 mITT

SA / NSTE-ACS / STEMI

P2Y12 naïve

Placebo or clopidogrel before or

after PCI

CHAMPION PCI

n=8,667 mITT

SA / NSTE-ACS / STEMI

Placebo or clopidogrel before PCI

CHAMPION PLATFORM

n=5,301 mITT

SA / NSTE-ACS

P2Y12 naïve

Placebo or clopidogrel after PCI

Cangrelor bolus then infusion

Cangrelor bolus then infusion

Clopidogrel 600 mg oral



Clopidogrel 600 mg or 300 mg oral


OR

Randomised, Double Blind, Controlled Trials of patients undergoing PCI

Harrington RA, et al. NEJM 2009

Bhatt DL, et al. NEJM 2009

Bhatt DL, et al. NEJM 2013

Death / MI / IDR / ST OR (95% CI) p value

p for

interaction

PLATFORM 0.72 (0.53, 0.97) 0.0330

PCI 0.90 (0.72, 1.14) 0.3859

PHOENIX 0.79 (0.67, 0.93) 0.0055

Pooled 0.81 (0.71, 0.91) 0.0007 0.4537

ST PLATFORM 0.31 (0.11, 0.85) 0.0157

PCI 0.73 (0.33, 1.59) 0.4242

PHOENIX 0.62 (0.43, 0.90) 0.0101

Pooled 0.59 (0.43, 0.80) 0.0008 0.3716

Death / MI / IDR PLATFORM 0.72 (0.53, 0.97) 0.0330

PCI 0.90 (0.72, 1.14) 0.3859

PHOENIX 0.80 (0.67, 0.95) 0.0115

Pooled 0.81 (0.71, 0.92) 0.0014 0.4681

Death / QMI / IDR PLATFORM 0.55 (0.33, 0.93) 0.0224

PCI 0.66 (0.42, 1.05) 0.0779

PHOENIX 0.76 (0.53, 1.11) 0.1558

Pooled 0.68 (0.52, 0.87) 0.0022 0.6093

Summary of Clinical Efficacy: Pooled Analysis

Comparator better Cangrelor better

Steg GS, Bhatt DL, Hamm CW et al…. Harrington RA. Lancet 2013.

Cangrelor

Mehta SR. Lancet 2013 at www.thelancet.com

Pooled CHAMPION Trials Overall and STEMI outcomes, 48 h

Primary Endpoint Cangrelor Clopidogrel OR

Overall mITT* (N=24,910) 473/12,459 (3.8%) 579/12,422 (4.7%) 0·81 (0.71-0.91)

STEMI† (n=2884) 41/1407 (2.9%) 51/1477 (3.5%) 0·84 (0.55-1.27)

Stent Thrombosis

Overall mITT* (N=24,881) 62/12,459 (0.5%) 105/12,422 (0.8%) 0·59 (0.43-0.80)

STEMI (n=2,884) 16/1407 (1.1%) 24/1477 (1.6%) 0.70 (0.37-1.32)

* Overall population includes CHAMPION PHOENIX, PCI, and PLATFORM; †STEMI population from PHOENIX and PCI

* Steg GS, Bhatt DL, Hamm CW et al…. Harrington RA. Lancet 2013; 82:1981–92.

GUSTO sev/mod bleeding

Overall safety* (N=25,107) 103 (0.8%) 79 (0.6%) 1·30 (0.97-1.75)

STEMI (n=3008) 17/1463 (1.2%) 15/1545 (1.0%) 1.20 (0.60-2.41)

0.1 1 10

0.1 1 10

0.1 1 10

Conclusions

• Dual antiplatelet therapy indicated for at least 1 year after ACS

• Likely benefit > 1 year in patients w/ prior MI – CHARISMA subgroup

• PEGASUS showed a significant reduction in CV death/MI/stroke

• PEGASUS also showed an increase in non-fatal bleeding

• DAPT data more nuanced, risks may outweigh benefits outside of ACS

• Duration for elective 2nd generation DES likely shorter, for ACS longer

• A year after ACS, in selected patients, 2 drugs are better than 1

• Important to individualize therapy based on ischemic/bleeding risks

Prior MI, CVA, or PAD

Vorapaxar

2.5 mg/d

Placebo

RANDOMIZE 1:1 DOUBLE BLIND

Follow up Visits

Day 30, Mo 4, Mo 8, Mo 12

Q6 months

Standard care

including oral antiplt rx

Final Visit

Key Inclusion:

1) Type 1 MI: 2 wks - 12 mo

2) Ischemic CVA: 2 wk - 12 mo

3) PAD: claudication + abnl

ABI or prior revasc

Trial Design

Stratified by:

1) Qualifying athero

2) Use of thienopyridine

DSMB observed risk of

ICH in Pts w/ stroke

Rec stopping study drug

in Pts w/ any h/o stroke

Primary Efficacy Evaluation

CV 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 R

ate

(%

)

Days since randomization

9.3%

10.5% Hazard Ratio 0.87;

95% CI 0.80 to 0.94

p < 0.001

N = 26449 Median f/u

2.5 years

Placebo

Vorapaxar

Morrow DA et al. NEJM 2012;366:1404-13

Vora Plac HR P-value

CV Death 2.7 3.0 0.89 0.15

MI 5.2 6.1 0.83 0.001

Stroke 2.8 2.8 0.97 0.73

Major Bleeding Endpoints

ARD 2.0%

HR 1.87

P<0.001

ARD 1.5%

HR 2.55

P<0.001

ARD 0.2%

HR 1.48

P=0.46

ARD 0.2%

HR 1.55

P=0.049

ARD 0.1%

HR 1.44

P=0.30

3-yr KM rate (%)

ARD 0.7%

HR 1.35

P=0.005

Prior Stroke

n = 5746

No Hx of Stroke

n = 20699

Morrow DA et al. NEJM 2012;366:1404-13

0%

2%

4%

6%

8%

10%

12%

0 360 720 1080

Even

t R

ate

(%

)

Days since Randomization

0%

1%

2%

3%

0 360 720 1080

Even

t R

ate

(%

)

Days since Randomization

HR 0.73

p = 0.02

Primary Efficacy Evaluation Low Bleeding Risk Cohort* (N= 14,909)

CV Death

6.8%

8.6%

Placebo

Vorapaxar

HR 0.75

p < 0.0001

CV Death, MI, or Stroke

1.5%

2.0%

*Age <75 y, no h/o stroke/TIA, wt ≥60 kg Scirica BM et al. Lancet 2012;380:1317-24

Efficacy Early and Late Prior MI Cohort

Days 0 to 360

0%

1%

2%

3%

4%

5%

6%

7%

0 90 180 270 360

CV

Death

/ M

I / S

tro

ke

(%)


Placebo

Vorapaxar 3.2%

4.0%

HR 0.79

p = 0.003

0%

1%

2%

3%

4%

5%

6%

7%

360 450 540 630 720 810 900 990 1080


Placebo

Vorapaxar

Day 360 to 1080

5.5%

6.5%

HR 0.82

p = 0.004

Scirica BM et al. Lancet 2012;380:1317-24

1.4%

Days from randomization

Even

t R

ate

(%

)

1.1%

Stent Thrombosis

By Randomized Treatment

ARC Definite Stent

Thrombosis

HR 0.71 (0.52 – 0.98)

P=0.04

Placebo

Vorapaxar

Bonaca et al. JACC 2014

Vorapaxar and Limb

Vascular Efficacy Hospitalization for

Acute Limb Ischemia Pre-specified, adjudicated

2.3%

3.9%

Hazard Ratio 0.58

95% CI 0.39 to 0.86

p = 0.006

Placebo

Vorapaxar

N = 3767


Peripheral

Revascularization Prespecified, Investigator

18.4%

22.2%

Hazard Ratio 0.84;

95% CI 0.73 to 0.97

p = 0.017

Bonaca et al. Circulation 2013;127:1522-9

Incidence of New Ischemic Stroke

0.88%

1.47%


Even

t R

ate

(%

)

P<0.001

Patients without history of Stroke/TIA

N = 20,170

Bonaca MP et al. JACC 2014

0.88%

1.47%

P<0.001

Ischemic stroke HR 0.57, p<0.001

Hemorrhagic stroke HR 2.78, p=0.049

Overall stroke HR 0.68, p=0.005

Patients with Prior MI

and No Hx of Stroke or TIA

-30

-20

-10

0

10

Eve

nts

/10

00

Pa

tie

nt/3

Ye

ars

MI CV

Death

Stroke Fatal Bleeding

Non-Fatal ICH

CV Death MI Stroke

-25

-14

-6 -5

0

+1

First Serious (Irreversible) Events

Risk Differences for 1000 Patients per 3 years- Vora vs. PBO

Braunwald E. Source: US FDA website - 20140115 CRDAC-S1-03




Yellow: sig ↓ w/short DAPT

Orange: sig ↑ w/short DAPT

≤6-month vs

1-year DAPT HR (95% CrI)

6-month vs

>1-year DAPT HR (95% CrI)

1-year vs

>1-year DAPT HR (95% CrI)

All-cause death 0.95 (0.76-1.20) 0.78 (0.59-1.00) 0.82 (0.65-1.00)

- Cardiac 0.96 (0.68-1.40) 0.90 (0.62-1.30) 0.93 (0.69-1.20)

- Non-cardiac 1.00 (0.69-1.60) 0.65 (0.41-1.00) 0.61 (0.42-0.87)

Myocardial infarction 1.00 (0.75-1.30) 1.70 (1.30-2.40) 1.70 (1.40-2.10)

Def/prob stent thrombosis 1.10 (0.66-1.70) 2.70 (1.50-5.00) 2.50 (1.70-4.00)

Major bleeding 0.59 (0.36-0.95) 0.34 (0.20-0.55) 0.58 (0.45-0.74)



Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.


Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.

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