New Drugs on the Horizon

New Drugs on the Horizon
Stephen G. Ellis, M.D.
Professor of Medicine
Cleveland Clinic Lerner College of Medicine
Conflict of Interest: none
Prepared in conjunction with Eric Bates, MD
What’s New in the Management of
Acute Coronary Disease and A Fib?
Agent
OR
Prasugrel (TRITON/T38)
Ticagrelor (PLATO)
Cangrelor (CHAMPION PCI)
Dabigatran (150mg)(RE-LY)
Rivaroxiban (ATLAS2/T51,
Rocket-AF)
Apixiban (APPRAISE-2,
ARISTOTLE)
Vorapaxar (TRACER)
* vs ASA+Clopidogrel
MACE
Bleeding
ACS/PCI*
AF**
ACS
AF
0.81
0.84
0.97/.80
-
0.65
1.3
1.0
1.0/1.5
0.9
0.84
0.79
3.0
1.2
0.95
0.92
0.79
-
2.6
1.3
0.7
-
** vs Warfarin
STRIVE
TM
What’s New in the Management of
Acute Coronary Disease and A Fib?
Agent
OR
Prasugrel (TRITON/T38)
Ticagrelor (PLATO)
Cangrelor (CHAMPION PCI)
Dabigatran (150mg)(RE-LY)
Rivaroxiban (ATLAS2/T51,
Rocket-AF)
Apixiban (APPRAISE-2,
ARISTOTLE)
Vorapaxar (TRACER)
* vs ASA+Clopidogrel
MACE
Bleeding
ACS/PCI*
AF**
ACS
AF
0.81
0.84
0.97/.80
-
0.65
1.3
1.0
1.0/1.5
0.9
0.84
0.79
3.0
1.2
0.95
0.92
0.79
-
2.6
1.3
0.7
-
** vs Warfarin
STRIVE
TM
Cangrelor
Parenteral ADP-P2Y12 receptor antagonist
 ATP
analogue
 Immediate
 Plasma
onset (within 5 minutes)
half-life of 5–9 minutes
 20–60
minutes for return to
normal platelet
function
N
4Na
+
O
O
O O
P
P
P
O
O
O
O
Cl Cl O
O
HO
Storey RF, et al. Thromb Haemost. 2001;85:401-47.
Greenbaum AB, et al. Am Heart J. 2006;151:689e1-689e10.
N
OH
S
HN
N
N
S
CF3
Effect of Cangrelor on ADP-induced Platelet
Aggregation in Patients with NSTE-ACS
Whole Blood Impedance Aggregometry
IPA, % (Mean ± SEM)
100
80
60
40
20
0
Incremental Infusion Doses
0.05 mg/
kg/min
0.2 mg/
kg/min
0.5 mg/
kg/min
0.5
1.5
2.5
2.0 mg/
kg/min
3.5
Time after onset of infusion, h
Storey RF et al. Thromb Haemost. 2001;85:401-07.
5
24
20 m
Post
1h
Post
Time after termination
of infusion
CHAMPION: Design of Trials
CHAMPION PCI
Start PCI
1 hr
2 hr
Cangrelor infusion
• n=9000
• SA/UA/NSTEMI/STEMI
• Not Thienopyridine Naive
R
* Enrollment stopped early by IARC;
Actual n=8885 (98% of planned)
End of PCI procedure
CHAMPION PLATFORM
Start PCI
1 hr
2 hr
Cangrelor infusion
• n=6400
• SA/UA/NSTEMI
• Thienopyridine Naive
R
* Enrollment stopped early by IARC;
Actual n=5362 (84% of planned)
End of PCI procedure
Screening
Randomization
Bhatt DL et al. N Engl J Med. 2009;361:2330-2341.
Drug Infusion
Follow - up
Harrington RA et al. N Engl J Med. 2009;361:2318-2329.
Champion: Summary of Clinical Efficacy
48-Hour Events
PLATFORM
Death/MI/IDR
Death/Q-MI/IDR
Death/Q-MI/ST
OR [95% CI]
P value
0.87 (0.71,1.07)
0.55 (0.33,0.93)
0.38 (0.20,0.72)
0.17
0.02
0.003
1.05 (0.89,1.24)
0.66 (0.42,1.05)
0.74 (0.43,1.27)
0.57
0.08
0.27
0.97 (0.86,1.11)
0.61 (0.43,0.86)
0.55 (0.36,0.83)
0.68
0.005
0.004
PCI
Death/MI/IDR
Death/Q-MI/IDR
Death/Q-MI/ST
POOLED
Death/MI/IDR
Death/Q-MI/IDR
Death/Q-MI/ST
0.2
0.5
Cangrelor Better
1.0
2.0
5.0
Comparator Better
1. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330-41.
2. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361:2318-29.
3. White HD, Chew DP, Dauerman HL, et al. AHJ 2012.
SGE; 0713-6, 30
CHAMPION PHOENIX Study Design
OR
Placebo3 oral (right before PCI or right after, per physician)
Cangrelor2 bolus & infusion (30ug/kg; 4ug/kg/min)
CHAMPION PHOENIX
Clopidogrel
600 mg oral
N = 10,900 MITT
SA/ NSTE-ACS/ STEMI
PCI ~30’
Rand
Patients requiring PCI1
Placebo2 bolus & infusion
P2Y12 inhibitor naïve
OR
0
Placebo oral
Clopidogrel3 (600 mg or 300 mg oral, per physician)
1
2 to 4 hours
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.
SGE;
0713-6, 11
Champion Phoenix: 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
Bhatt DL, et al. NEJM 2013;368:1303-13.
5229
5159
5225
5155
5223
5152
5221
5151
5220
5151
5217
5147
5213
5147
Event Rate (%)
Champion Phoenix: Stent
Thrombosis within 48 Hours
clopidogrel
1.4%
0.8%
cangrelor
Log Rank P Value = 0.01
Patient at Risk
Cangrelor:
Clopidogrel:
Hours from Randomization
5472
5470
5426
5392
Bhatt DL, et al. NEJM 2013;368:1303-13.
5421
5389
5419
5388
5419
5386
5418
5385
5417
5385
5416
5383
5414
5383
Subgroups: Death/MI/IDR/ST at 48 Hours
Overall
OR [95% CI]
0.79 (0.67,0.93)
Age ≥75
Age <75
0.71 (0.50,1.02)
0.81 (0.67,0.98)
0.55
Male
Female
0.84 (0.69,1.03)
0.67 (0.50,0.92)
0.23
Ethnicity: White
Ethnicity: Non-white
0.80 (0.67,0.95)
0.70 (0.35,1.41)
0.72
United States
Other Countries
0.70 (0.53,0.92)
0.85 (0.69,1.05)
0.26
Stable Angina
NSTE-ACS
STEMI
0.78 (0.63,0.95)
0.80 (0.55,1.17)
0.75 (0.46,1.25)
0.98
Weight >=60
Weight <60
0.79 (0.66,0.94)
0.75 (0.39,1.45)
0.89
Biomarker Positive
Biomarker Negative
0.90 (0.64,1.27)
0.75 (0.61,0.91)
0.35
Diabetic No
Diabetic Yes
0.74 (0.61,0.90)
0.92 (0.67,1.27)
0.26
Insulin-Dependent Diabetes: Yes
Insulin-Dependent Diabetes: No
0.74 (0.42,1.31)
0.79 (0.66,0.94)
0.82
Prior MI
No Prior MI
0.68 (0.47,0.97)
0.84 (0.69,1.02)
0.30
0.2
Cangrelor Better
1.0
Clopidogrel Better
P [Int]
5.0
SGE; 0713-6, 17
Subgroups: Death/MI/IDR/ST at 48 Hours (continued)
OR [95% CI]
P [Int]
Prior TIA/Stroke
No Prior TIA/Stroke
0.78 (0.37,1.63)
0.79 (0.66,0.94)
0.97
History of PAD
No History of PAD
0.36 (0.21,0.63)
0.86 (0.72,1.03)
0.003
History of CHF
No History of CHF
0.73 (0.45,1.20)
0.80 (0.67,0.96)
0.74
Clopidogrel 300 mg
Clopidogrel 600 mg
0.84 (0.62,1.14)
0.77 (0.63,0.94)
0.62
Bivalirudin only
Heparin only
0.69 (0.47,1.01)
0.80 (0.65,0.98)
0.51
Femoral
Radial
0.79 (0.65,0.96)
0.76 (0.54,1.06)
0.83
# vessels =1
# vessels ≥2
0.80 (0.66,0.97)
0.70 (0.49,0.99)
0.51
Drug-Eluting Stent
Bare-Metal Stent
0.80 (0.64,1.01)
0.77 (0.60,0.99)
0.79
Aspirin ≤100 mg
Aspirin >100 mg
0.80 (0.63,1.00)
0.70 (0.52,0.94)
0.49
Clopidogrel Load before PCI Start
Clopidogrel Load after PCI Start
0.80 (0.64,0.98)
0.79 (0.59,1.06)
0.99
Cangrelor infusion ≤ 129 minutes
Cangrelor infusion > 129 minutes
0.85 (0.68,1.07)
0.72 (0.56,0.92)
0.31
0.2
Cangrelor Better
1.0
Clopidogrel Better
5.0
SGE; 0713-6, 18
Non-CABG Bleeding at 48 Hours, Safety
Cangrelor
(N=5529)
Clopidogrel
(N=5527)
OR (95% CI)
P Value
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
Bleeding Scale
GUSTO Severe
Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013 at www.nejm.org
SGE; 0713-6, 19
Subgroups: GUSTO Severe/Moderate Bleeding, Safety
Overall
OR [95% CI]
P [Int]
1.63 (0.92,2.90)
Age ≥75
Age <75
1.07 (0.45,2.53)
2.24 (1.02,4.93)
0.21
Male
Female
0.93 (0.41,2.12)
2.75 (1.16,6.51)
0.07
Ethnicity: White
Ethnicity: Non-white
1.86 (0.97,3.56)
1.02 (0.29,3.56)
0.40
United States
Other Countries
1.34 (0.56,3.18)
1.90 (0.88,4.10)
0.55
Stable Angina
NSTE-ACS
STEMI
1.45 (0.59,3.56)
1.79 (0.52,6.13)
1.84 (0.72,4.70)
0.93
Weight >=60
Weight <60
1.52 (0.80,2.86)
2.01 (0.52,7.86)
0.71
Biomarker Positive
Biomarker Negative
1.51 (0.64,3.53)
1.76 (0.81,3.82)
0.79
Diabetic No
Diabetic Yes
1.90 (0.88,4.09)
1.35 (0.57,3.20)
0.56
Insulin-Dependent Diabetes: Yes
Insulin-Dependent Diabetes: No
3.56 (0.40,32.00)
1.52 (0.83,2.76)
0.45
Prior MI
No Prior MI
3.25 (0.65,16.12)
1.44 (0.78,2.67)
0.35
0.2
Cangrelor Better
1.0
5.0
Clopidogrel Better
SGE; 0713-6, 20
Subgroups: GUSTO Severe/Moderate Bleeding, Safety
(continued)
OR [95% CI]
P [Int]
Prior TIA/Stroke
No Prior TIA/Stroke
0.92 (0.13,6.55)
1.72 (0.94,3.13)
0.54
History of PAD
No History of PAD
NA
1.55 (0.84,2.87)
0.10
History of CHF
No History of CHF
2.13 (0.39,11.70)
1.79 (0.95,3.37)
0.85
Clopidogrel 300 mg
Clopidogrel 600 mg
4.02 (1.13,14.27)
1.19 (0.61,2.31)
0.09
Bivalirudin only
Heparin only
0.86 (0.26,2.83)
1.89 (0.91,3.93)
Femoral
Radial
1.68 (0.90,3.11)
1.37 (0.31,6.11)
0.81
# vessels =1
# vessels ≥2
1.81 (0.94,3.49)
1.12 (0.34,3.68)
0.48
Drug-Eluting Stent
Bare-Metal Stent
1.26 (0.57,2.77)
2.17 (0.93,5.03)
0.35
Aspirin ≤100 mg
Aspirin >100 mg
1.58 (0.52,4.85)
1.49 (0.74,3.03)
0.93
Clopidogrel Load before PCI Start
Clopidogrel Load after PCI Start
1.24 (0.58,2.66)
2.53 (0.98,6.54)
0.25
Cangrelor infusion ≤ 129 minutes
Cangrelor infusion > 129 minutes
1.71(0.81,3.59)
1.52(0.62,3.73)
0.85
0.2
1.0
Cangrelor Better
0.26
5.0
Clopidogrel Better
SGE; 0713-6, 21
Rivaroxaban
• Oral factor Xa inhibitor
• Activation: None
• Tmax: 2-4 hours
• T1/2: 5-9 hours
• Metabolism: Hepatic,CYP3A4
• Renal excretion: 66%
• Dosing: Fixed, once daily
• Monitoring: None required
Recent ACS: STEMI, NSTEMI, UA
Stabilized 1-7 Days Post-Index Event
Exclusions: increased bleeding risk, warfarin use, ICH,
prior stroke if on ASA + thienopyridine
ASA 75 to 100 mg/day
Stratified by Thienopyridine Use at MD Discretion
Placebo
n=5,176
Rivaroxaban
Rivaroxaban
2.5 mg BID
5.0 mg BID
n=5,174
n=5,176
PRIMARY ENDPOINTS:
EFFICACY: CV Death, MI, Stroke (Ischemic, Hemorrhagic, or Uncertain Origin)
SAFETY: TIMI major bleeding not associated with CABG
Event driven trial with 1,002 primary efficacy events
PRIMARY EFFICACY ENDPOINT:
CV Death / MI / Stroke
Estimated Cumulative Incidence (%)
2 Yr KM Estimate
No. at Risk
Placebo
Rivaroxaban
Placebo
10.7%
8.9%
HR 0.84
(0.74-0.96)
Rivaroxaban
(both doses)
mITT p = 0.008
ITT p = 0.002
ARR 1.8%
NNT = 56
Months After Randomization
5113
4307
3470
2664
1831
1079
421
10229
8502
6753
5137
3554
2084
831
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.
STENT THROMBOSIS
ARC Definite / Probable / Possible
Estimated Cumulative Incidence (%)
2 Yr KM Estimate
Placebo
2.9%
2.3%
HR 0.69
Rivaroxaban
(both doses)
ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012
Months After Randomization
(0.51- 0.93)
mITT p = 0.016
ITT p = 0.008
EFFICACY ENDPOINTS:
Low Dose 5.0 mg BID
CV Death / MI / Stroke
Estimated Cumulative Incidence (%)
HR 0.85
10
Cardiovascular Death
Placebo
10.7%
mITT
p=0.028
ITT
p=0.010
HR 0.94
Placebo
4.1%
mITT
p=0.63
ITT
p=0.57
8.8%
4.0%
5
Rivaroxaban
5 mg BID
Rivaroxaban
5 mg BID
NNT=53
0
0
1
24
Months
0
Months
24
EFFICACY ENDPOINTS:
Very Low Dose 2.5 mg BID
CV Death / MI / Stroke
All Cause Death
Cardiovascular Death
5%
5%
Estimated Cumulative incidence (%)
12%
HR 0.84
HR 0.66
Placebo
10.7%
mITT
p=0.020
4.1%
mITT
p=0.002
9.1%
ITT
p=0.007
HR 0.68
Placebo
Placebo
mITT
p=0.002
4.5%
ITT
p=0.004
ITT
p=0.005
2.9%
2.7%
0
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
NNT = 63
NNT = 71
NNT = 63
12
Months
24
0
12
Months
24
0
12
Months
24
EFFICACY ENDPOINTS:
Very Low Dose 2.5 mg BID
Patients Treated with ASA + Thienopyridine
CV Death / MI / Stroke
Estimated Cumulative incidence (%)
12%
HR 0.85
All Cause Death
Cardiovascular Death
5%
5%
HR 0.62
Placebo
mITT
p=0.039
mITT
p<0.001
10.4%
HR 0.64
Placebo
4.2%
Placebo
mITT
p<0.001
4.5%
9.0%
ITT
p=0.011
ITT
p<0.001
ITT
p<0.001
2.7%
2.5%
0
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
Rivaroxaban
2.5 mg BID
NNT = 71
NNT = 59
NNT = 56
12
Months
24
0
12
Months
24
0
12
Months
24
SAFETY ENDPOINTS
Treatment-Emergent Non CABG TIMI Major Bleeding*
Analysis
2 Yr KM Estimate
Placebo
2.5 mg
Rivaroxaban
5.0 mg
Rivaroxaban
0.6%
1.8%
2.4%
HR 3.46
HR 4.47
p<0.001
p<0.001
Liver Function Test (ALT > 3xULN) #
ALT > 3X ULN
1.6%
1.3%
1.4%
p=NS
p=NS
There was no excess of either combined ALT > 3x ULN and Total Bilirubin > 2x ULN cases
among patients treated with Rivaroxaban, or SAEs.
Post-Treatment CVD / MI / Stroke##
1-10 Days After Last
Dose
1.8%
1.4%
2.2%
p=NS
p=NS
*: First occurrence of Non-CABG TIMI major bleeding events occurred between first dose to 2 days post last dose 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 are provided; Stratified log-rank p-values
are provided; #: Raw percentage of subjects with abnormal value measured between first dose to 2 days post last dose among subjects with normal baseline
measurement; ##: Raw percentage.
New Drug Challenges
 Cangrelor
 Cost
 Same benefit may be achieved by substituting prasugrel or
ticagrelor for clopidogrel as DAPT
 Same onset may be achieved by bolus GP IIb/IIIa without
infusion (but cangrelor has quicker offset)
 Rivaroxaban
 Same benefit may be achieved by substituting prasugrel or
ticagrelor for clopidogrel as DAPT
 Difficult to promote triple therapy for ACS since other studies in
this field have shown bleeding risk
New Drugs- Summary
Cangrelor
Seems to have niche for ACS patients
- need DAPT early d/t risk*
- delay for cath
- may need CABG
Rivaroxaban
Uncertain benefit
- not studied vs prasugrel or ticagrelor
- more bleeding than clopidogrel
* pretreatment associated with OR=0.77 for MACE and 1.2 for
bleeding in 2012 meta-analysis (JAMA 308:2507,’12)