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
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
Vorapaxar
ACS & Plaque Rupture
Platelet
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.
Granule
Secretion
Amplification
P2Y
12
ADP
Thrombin
Vorapaxar
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Aspirin
TxA2
Collagen/vWF
ACS & Plaque Rupture
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
Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.
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
Bonaca MP, Bhatt DL, Cohen M, et al. NEJM. 2015.
PEGASUS – TIMI 54
Bonaca MP, Bhatt DL, Cohen M, et al. NEJM. 2015.
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.
CHARISMA 53 1903 65 1943 PRODIGY 31 732 31 733 ARCTIC-Int’n 0 156 1 167 DAPT 11 1805 16 1771 DES-LATE 21 1512 21 1551 PEGASUS 356 14095 210 7067
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)
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
0.85 (0.74 - 0.98)
Cardiovascular Death
Udell JA, Bonaca MP, Collet JP, et al. Eur Heart J 2015.
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
Udell JA, Bonaca MP, Collet JP, et al. Eur Heart J 2015.
CHARISMA 45 1903 39 1943 PRODIGY 9 732 6 733 ARCTIC-Int’n 2 156 0 167 DAPT 34 1805 14 1771 DES-LATE 39 1512 31 1551 PEGASUS 242 13946 54 6996
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)
Study Events Total Events Total
Extended Aspirin Risk Ratio
DAPT Alone (95% CI)
0.5 1 2 5 Extended DAPT Better Aspirin Alone Better
1.73 (1.19 - 2.50)
Major Bleeding
Udell JA, Bonaca MP, Collet JP, et al. Eur Heart J 2015.
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
No Pre-treatment 1.5
No Pre-treatment 1.4
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.
Oral Pretreatment in STEMI
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
Favors NOAC Favors Warfarin
0.2 0.5 1 2
Secondary Efficacy Outcomes
Heterogeneity p=NS for all outcomes
Ruff CT, et al. Lancet 2014;383:955-962
ARISTOTLE
ROCKET AF
Combined
Favors NOAC Favors Warfarin
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]
Ruff CT, et al. Lancet 2014;383:955-962
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
Favors NOAC Favors Warfarin
0.2 0.5 1 2
Secondary Safety Outcomes
Heterogeneity
ICH, p=0.22
GI Bleeding, p=0.009
Ruff CT, et al. Lancet 2014;383:955-962
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
Clopidogrel 75 mg qd†
Aspirin 75-100 mg qd‡
VKA (target INR 2.0-3.0)
Aspirin 75-100 mg qd
VKA (target INR 2.0-3.0)
Clopidogrel 75 mg qd†
Aspirin 75-100 mg qd
≤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
Months Since Randomization
0 6 12 18 24 30
Clopidogrel + ASA
Placebo + ASA
N=9,478
* Post hoc analysis.
Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.
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
(%
)
Months Since Randomization
6.3%
5.7%
Placebo + ASA
Clopidogrel + ASA
Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.
PEGASUS TIMI 54 – Other Efficacy Outcomes
Bonaca MP, Bhatt DL, Cohen M, et al. NEJM. 2015.
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
Udell JA, Bonaca MP, Collet JP, et al. Eur Heart J 2015.
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.
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
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
Mauri L, et al. NEJM 2014
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
Mortality with Extended Duration DAPT After
DES: A Pairwise and Bayesian Network
Meta-Analysis of 10 RCTs and 31,666 Pts
41% ↓
stent
thrombosis
with
prolonged
DAPT
(p=0.06)
Definite/
Probable ST HR
(95% CI)
DAPT
EXCELLENT
ISAR SAFE
ITALIC
OPTIMIZE
PRODIGY
RESET
SECURITY
I-V (I2=43.7%, p=0.09); p value for ES<0.0001
2 .1 3
Shorter DAPT better
5 1 .5
Longer DAPT better
D+L: p value for ES=0.06
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
Palmerini T, ….Stone GW. Lancet 2015:on-line
Mortality with Extended Duration DAPT After
DES: A Pairwise and Bayesian Network
Meta-Analysis of 10 RCTs and 31,666 Pts
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
D+L: p value for ES=0.52
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
Palmerini T, ….Stone GW. Lancet 2015:on-line
Mortality with Extended Duration DAPT After
DES: A Pairwise and Bayesian Network
Meta-Analysis of 10 RCTs and 31,666 Pts
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
I-V (I2=0.0%, p=0.83); p value for ES<0.0001
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
Palmerini T, ….Stone GW. Lancet 2015:on-line
Mortality with Extended Duration DAPT After
DES: A Pairwise and Bayesian Network
Meta-Analysis of 10 RCTs and 31,666 Pts
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
I-V (I2=0.0%, p=0.71); p value for ES=0.006
2 .1 3
Shorter DAPT better
5 1 .5
Longer DAPT better
D+L: p value for ES=0.006
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
Palmerini T, ….Stone GW. Lancet 2015:on-line
Mortality with Extended Duration DAPT After
DES: A Pairwise and Bayesian Network
Meta-Analysis of 10 RCTs and 31,666 Pts
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
I-V (I2=0.0%, p=0.93); p value for ES=0.02
2 .1 3 5 1 .5
Longer DAPT better
D+L: p value for ES=0.02
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
Palmerini T, ….Stone GW. Lancet 2015:on-line
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 oral
Clopidogrel 600 mg oral
Clopidogrel 600 mg or 300 mg oral
Clopidogrel 600 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
(%)
Days since randomization
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
Days since randomization
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
Days from randomization
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%
Days from randomization
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
Mortality with Extended Duration DAPT After
DES: A Pairwise and Bayesian Network
Meta-Analysis of 10 RCTs and 31,666 Pts
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)
Palmerini T, ….Stone GW. Lancet 2015:on-line
Oral Pretreatment in STEMI
Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.
Oral Pretreatment in STEMI
Ghobrial J, Gibson CM, Pinto DS. Journal of Invasive Cardiology 2015;27(5):E68-E69.