. ; .

, MD, FESC, FAHA

- . -

 , ab, AstraZeneca, Bayer, Sanofi, Pfizer, Vianex, MSD, Unilever, Boehringer, Novartis, Abbott, Galenica, Specifar, Menarini, Merck, Pharmaswiss, Winmedica, Amgen

Timing of Benefit (Landmark Analysis)

8

Primary Endpoint (%)

Clopidogrel
6

Clopidogrel 5.6 4.7

6.9 5.6

Prasugrel
2

Prasugrel HR 0.80 P=0.003

1

HR 0.82 P=0.01

30 60 90

180

270

360

450

Loading Dose

Days

Maintenance Dose

Stent Thrombosis
(ARC Definite + Probable)
3
Any Stent at Index PCI N= 12,844

Clopidogrel

2.4 (142)

Endpoint (%)

1 Prasugrel

1.1 (68)
HR 0.48 P <0.0001 NNT= 77

0 30 60 90

180 Days

270

360

450

Platelet inhibition and patient Outcomes: Study design1,2

UA/NSTEMI (moderate-high risk) and STEMI (if primary PCI) All receiving ASA Clopidogrel treated or nave Randomised within 24 hours of index event N = 18,624

If pretreated, no additional loading dose If nave, standard 300 mg loading dose 75 mg OD maintenance (additional 300 mg allowed pre-PCI)

Clopidogrel

180 mg loading dose 90 mg bd maintenance (additional 90 mg allowed pre-PCI)

Ticagrelor

6-12 months treatment

1. Adapted from James S, et al. Am Heart J 2009;157:599-605. 2. Adapted from Wallentin L, et al. N Eng J Med 2009; 361(11):1045-1057.

Kaplan-Meier estimate of time to first primary efficacy endpoint (composite of CV death, MI or stroke)1

Wallentin L, et al. N Engl J Med 2009;361:1045-1057

Major secondary efficacy endpoints

Ticagrelor (n = 9333)

Clopidogrel (n = 9291)

HR (95% CI)

p value

Primary endpoint, n (%)* CV death + MI + stroke Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events MI CV death Stroke Total death 864 (9.8) 901 (10.2) 1290 (14.6) 1014 (11.7) 1065 (12.3) 1456 (16.7) 0.84 (0.77-0.92) 0.84 (0.77-0.92) 0.88 (0.81-0.95) <0.001 < 0.001 < 0.001 Secondary endpoints, n (%)

504 (5.8) 353 (4.0) 125 (1.5) 399 (4.5)

593 (6.9) 442 (5.1) 106 (1.3) 506 (5.9)

0.84 (0.75-0.95) 0.79 (0.69-0.91) 1.17 (0.91-1.25) 0.78 (0.69-0.89)

0.005 0.001 0.22 <0.001

* Percentages are Kaplan-Meier estimates of the endpoint at 12 months Nominal p value

Wallentin L, et al. N Engl J Med 2009;361:1045-1057.

PLATO Major Bleeding

13 12 11 10 9 8 7 6 5 4 3 2 1 0
NS 11.6 11.2 NS NS 7.9 7.7 NS 5.8 5.8 8.9 8.9

K-M estimated rate (% per year)

Ticagrelor Clopidogrel

NS
0.3 0.3

PLATO major bleeding

TIMI major bleeding

Red cell transfusion

PLATO lifethreatening/ fatal bleeding

Fatal bleeding

Wallentin L, et al. N Engl J Med 2009;361:1045-1057.

CHAMPION PHOENIX Study Design

OR CHAMPION PHOENIX N = 10,900 MITT SA/ NSTE-ACS/ STEMI Patients requiring PCI1 P2Y12 inhibitor nave
Rand

Placebo3 oral (right before PCI or right after, per physician) Clopidogrel 600 mg oral

Cangrelor2 bolus & infusion (30ug/kg; 4ug/kg/min) PCI ~30 Placebo2 bolus & infusion OR

Placebo oral

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

0
1Randomization

2 to 4 hours

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.

Death/ MI/ IDR/ Stent Thrombosis within 48 Hours

Event Rate (%)

clopidogrel

5.9% 4.7%

cangrelor

Log Rank P Value = 0.006

Patient at Risk Cangrelor: Clopidogrel:

Hours from Randomization

5472 5470 5233 5162 5229 5159 5225 5155 5223 5152 5221 5151 5220 5151 5217 5147 5213 5147

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

Efficacy Outcomes at 30 Days, MITT

Cangrelor (N=5472) Clopidogrel (N=5470) 380/5457 (7.0%) 104/5457 (1.9%) 272/5457 (5.0%) 22/5457 (0.4%) 66/5457 (1.2%) 55/5457 (1.0%) 46/5457 (0.8%) OR (95% CI) P Value 0.03 0.01 0.03 0.18 0.36 0.64 0.84

Death/MI/IDR/ST (primary endpoint, adjusted)

Stent thrombosis MI Q-wave MI IDR Death CV Death

326/5462 (6.0%) 71/5462 (1.3%) 225/5462 (4.1%) 14/5462 (0.3%) 56/5462 (1.0%) 60/5462 (1.1%) 48/5462 (0.9%)

0.85 (0.73,0.99) 0.68 (0.50,0.92) 0.82 (0.68,0.98) 0.63 (0.32,1.24) 0.85 (0.59,1.21) 1.09 (0.76,1.58) 1.04 (0.69,1.57)

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

Non-CABG Bleeding at 48 Hours, Safety

Bleeding Scale
GUSTO Severe GUSTO Moderate GUSTO Severe + Moderate TIMI Major TIMI Minor TIMI Major + Minor Any Blood Transfusion

Cangrelor Clopidogrel (N=5529) (N=5527)

9 (0.16%) 22 (0.4%) 31 (0.6%) 5 (0.1%) 9 (0.2%) 14 (0.3%) 25 (0.5%) 6 (0.11%) 13 (0.2%)

OR (95% CI)
1.50 (0.53,4.22) 1.69 (0.85,3.37) 1.63 (0.92,2.90) 1.00 (0.29,3.45) 3.00 (0.81,11.10) 1.75 (0.73,4.18) 1.56 (0.83,2.93)

P Value
0.44 0.13 0.09 >0.999 0.08 0.2 0.16

19 (0.3%)
5 (0.1%) 3 (0.1%) 8 (0.1%) 16 (0.3%)

ACUITY Major ACUITY w/out hematoma

235 (4.3%) 42 (0.8%)

139 (2.5%) 26 (0.5%)

1.72 (1.39,2.13) 1.62 (0.99,2.64)

<0.001 0.05

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

Conclusions
In CHAMPION PHOENIX, intravenous ADP receptor antagonism with cangrelor significantly (p=0.005) reduced the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours, with a 22% odds reduction. The key secondary endpoint of stent thrombosis was also significantly reduced, with a 38% odds reduction. The benefit was sustained through 30 days. There was no excess in severe bleeding or transfusions. Intravenous cangrelor may be an attractive option across the full spectrum of PCI, including stable angina, NSTEMI, and STEMI.

PRIMARY EFFICACY ENDPOINT:

CV Death / MI / Stroke* (Ischemic + Hemg.)
2 Yr KM Estimate

Estimated Cumulative Rate (%)

Placebo

10.7% 8.9%
HR 0.84 (0.74-0.96) ARR 1.7%
mITT p = 0.008 ITT p = 0.002

Rivaroxaban
(both doses)

NNT = 59

No. at Risk Placebo Rivaroxaban

Months After Randomization

5113 4307 8502 3470 6753 2664 5137 1831 3554 1079 2084 421 831

10229

*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; ARR=Absolute Relative Reduction; NNT=Number needed to treat; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

STENT THROMBOSIS*
ARC Definite, Probable, Possible 2 Yr KM Estimate Estimated Cumulative incidence (%)

Placebo

2.9% 2.3%

HR 0.69 Rivaroxaban
(both doses)
(0.51- 0.93)
mITT p = 0.016 ITT p = 0.008

ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012

Months After Randomization

* End point events are as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

PRIMARY EFFICACY ENDPOINT*: 2.5 mg PO BID

CV Death / MI / Stroke*
5% 12%

Cardiovascular Death
5%

All Cause Death HR 0.68

4.1%

Estimated Cumulative incidence (%)

HR 0.84

Placebo
10.7% 9.1%

HR 0.66

Placebo

Placebo
4.5%

mITT p=0.020
ITT p=0.007

mITT p=0.002
ITT p=0.005

mITT p=0.002
ITT p=0.004

2.7%

2.9%

Rivaroxaban 2.5 mg BID

NNT = 63
0

Rivaroxaban 2.5 mg BID

NNT = 71
0

Rivaroxaban 2.5 mg BID

NNT = 63
0

12 Months

24

12 Months

24

12 Months

24

* First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat.

 RE-LY
1 A 951 44

PROBE=

Warfarin (INR 2.0-3.0) N=6000

Dabigatran Etexilate 110 mg N=6000

Dabigatran Etexilate 150 mg N=5000

10 = 10 = Non-inferiority margin 1.46

p-value

p-value 0.30

Dabigatran 110 vs. Warfarin

<0.001

Dabigatran 150 vs. Warfarin

<0.001

<0.001

Margin = 1.46

0.50

0.75

1.00

1.25

1.50

HR (95% CI)


D 110mg D 150mg warfarin
D 110 mg vs. Warfarin RR 95% CI 1.14 0.90-1.43 0.31 0.17-0.56 1.11 0.89-1.40 D 150 mg vs. Warfarin RR 95% CI 0.76 0.59-0.98 0.26 0.14-0.49 0.76 0.60-0.98

Number rate/yr 152 1.29 %/yr 14 0.1 %/yr 159 1.3 %/yr

Number rate/yr 103 0.9 %/yr 12 0.1 %/yr 111 0.9 %/yr

Number rate/yr 133 1.1 %/yr 45 0.4 %/yr 142 1.2 %/yr

0.28

0.03

I/

<0.001

<0.001

0.32

0.03


Dabigatran 110mg Dabigatran 150mg warfarin D 110mg vs. Warfarin RR 95% CI D 150mg vs. Warfarin RR 95% CI

()

1.1 %

1.5 %

1.0 %

1.10 0.86-1.41
0.31 0.20-0.47

0.43

1.50 1.19-1.89
0.40 0.27-0.60

<0.001

M
( , )

0.2 %

0.3 %

0.7 %

<0.001

<0.001

1.5 %

1.5 %

1.8 %

0.85 0.70-1.04

0.11

0.87 0.71-1.06

0.16


Dabigatran 110 mg % 11.8 9.3 8.1 7.9 6.6 5.7 5.2 4.5 5.3 5.6 6.3 5.5 4.5 4.8 Dabigatran 150 mg % 11.3 9.5 8.3 7.9 6.6 5.7 6.2 5.5 5.2 5.4 6.5 5.9 4.8 4.7 Warfarin % 5.8 9.7 9.4 7.8 6.2 6.0 5.9 5.7 5.6 5.6 5.7 5.8 5.6 5.2

* A

* dabigatran p<0.001

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke
Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension

Randomize double blind, double dummy (n = 18,201)

Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine

Apixaban 5 mg oral twice daily

(2.5 mg BID in selected patients)

Warfarin
(target INR 2-3)

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism
Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

Primary Outcome
Stroke (ischemic or hemorrhagic) or systemic embolism

P (non-inferiority)<0.001 21% RRR

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.660.95); P (superiority)=0.011

No. at Risk Apixaban Warfarin

9120 9081

8726 8620

8440 8301

6051 5972

3464 3405

1754 1768

Efficacy Outcomes
Apixaban Warfarin (N=9120) (N=9081) Event Rate Event Rate (%/yr) (%/yr) 1.27 1.19 0.97 0.24 0.09 1.60 1.51 1.05 0.47 0.10

Outcome

HR (95% CI)

P Value
0.011 0.012 0.42 <0.001 0.70

Stroke or systemic embolism* Stroke Ischemic or uncertain Hemorrhagic Systemic embolism (SE)

0.79 (0.66, 0.95) 0.79 (0.65, 0.95) 0.92 (0.74, 1.13) 0.51 (0.35, 0.75) 0.87 (0.44, 1.75)

All-cause death*
Stroke, SE, or all-cause death Myocardial infarction

3.52
4.49 0.53

3.94
5.04 0.61

0.89 (0.80, 0.998)

0.89 (0.81, 0.98) 0.88 (0.66, 1.17)

0.047
0.019 0.37

* Part of sequential testing sequence preserving the overall type I error

Major Bleeding
ISTH definition

31% RRR

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.600.80); P<0.001

No. at Risk Apixaban Warfarin

9088 9052

8103 7910

7564 7335

5365 5196

3048 2956

1515 1491

Compared with warfarin, apixaban (over 1.8 years) prevented

6 Strokes 15 Major bleeds 8 Deaths

per 1000 patients treated.

4 hemorrhagic 2 ischemic/uncertain type

Phase III ROCKET-AF: randomized, double-blind, non-inferiority study

AF with 2 or 3 risk factors* OR stroke, TIA or systemic embolus

R
Rivaroxaban 20 mg OD (15 mg OD for CrCl 3049 mL/min)

N=14 264; double blind 45 countries, 1178 sites

Warfarin INR target 2.5 (2.03.0 inclusive)

Primary outcomes: any stroke or non-CNS systemic embolism and composite of major and clinically relevant non-major bleeding events Secondary outcomes: each category of bleeding events and adverse events; and composite of stroke, non-CNS systemic embolism and vascular death
*Risk factors included congestive heart failure, hypertension, age 75 years, diabetes; enrolment of patients without prior stroke, TIA or systemic embolism and only 2 factors capped at 10% CrCl = creatinine clearance; OD = once daily; TIA = transient ischaemic attack

Mahaffey KW et al. Presented at AHA 2010; Session LBCT02 21839; Available at: http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#rocket
Disclaimer: Rivaroxaban is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only.

34 June 2011

ROCKET-AF: baseline characteristics (I)

Rivaroxaban (N=7081) Average age, yrs (range) Female Mean CHADS2 score 73 (6578) 40 3.48 Warfarin (N=7090) 73 (6578) 40 3.46

2
3 4 5 6

13
43 29 13 2

13
44 28 12 2

Prior VKA use

CHF Hypertension Diabetes mellitus Prior stroke/TIA/embolism Prior myocardial infarction

62
63 90 40 55 17

63
62 91 39 55 18

Based on intention-to-treat population; values are % unless otherwise stated. CHF = congestive heart failure; TIA = transient ischaemic attack; VKA = vitamin K antagonist

Mahaffey KW et al. Presented at AHA 2010; Session LBCT02 21839; Available at: http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#rocket

Disclaimer: Rivaroxaban is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only.

35 June 2011

ROCKET-AF: stroke and non-CNS embolism non-inferiority analysis

6 Cumulative event rate (%) 5 4 3 2 1
Warfarin Rivaroxaban HR 0.79 (95% CI: 0.660.96) P<0.001 (non-inferiority) Event rate Rivaroxaban 1.71 Warfarin 2.16

0
Number at risk Rivaroxaban Warfarin

120
6211 6327

240
5786 5911

360
5468 5542

480
4406 4461

600
3407 3478

720
2472 2539

840
1496 1538

960
634 655

Days from randomization

6958 7004

Event rates per 100 patient-years; based on protocol compliant on-treatment population

Mahaffey KW et al. Presented at AHA 2010; Session LBCT02 21839; Available at: http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#rocket
Disclaimer: Rivaroxaban is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only.

36 June 2011

ROCKET-AF: primary safety outcomes (I)

Outcome Rivaroxaban event rate Warfarin event rate HR (95% CI) P value

Major and non-major clinically relevant bleeding

14.91

14.52

1.03 (0.961.11)

0.442

Major bleeding

3.60

3.45

1.04 (0.901.20)
1.04 (0.961.13)

0.576

Non-major clinically relevant bleeding

11.80

11.37

0.345

Event rates per 100 patient-years; based on safety on-treatment population CI = confidence interval; HR = hazard ratio

Mahaffey KW et al. Presented at AHA 2010; Session LBCT02 21839; Available at: http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#rocket
Disclaimer: Rivaroxaban is not approved for clinical use in stroke prevention in atrial fibrillation. This information is provided for medical education purposes only.

37 June 2011

Vorapaxar approval status FDA July 24, 2013 Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the New Drug Application (NDA) for its investigational anti-thrombotic medicine, vorapaxar, has been accepted for standard review by the U.S. Food and Drug Administration (FDA). Merck is seeking FDA approval of vorapaxar for the secondary prevention of cardiovascular events in patients with a history of heart attack and no history of stroke or transient ischemic attack (TIA) EMA Submission 2013