horizons 1year pharm
TRANSCRIPT
-
8/14/2019 Horizons 1Year Pharm
1/33
A Prospective, Randomized Comparison ofA Prospective, Randomized Comparison of
Bivalirudin vs. Heparin Plus GlycoproteinBivalirudin vs. Heparin Plus Glycoprotein
IIb/IIIa Inhibitors During Primary Angioplasty inIIb/IIIa Inhibitors During Primary Angioplasty in
Acute Myocardial InfarctionAcute Myocardial Infarction
One Year Results One Year Results
Roxana Mehran MDRoxana Mehran MDFor the HORIZONS-AMI InvestigatorsFor the HORIZONS-AMI Investigators
-
8/14/2019 Horizons 1Year Pharm
2/33
Background
Numerous studies have demonstrated a strongNumerous studies have demonstrated a strong
association between hemorrhagic complications andassociation between hemorrhagic complications andsubsequent mortality in pts with ACS and after PCIsubsequent mortality in pts with ACS and after PCI
In the HORIZONS-AMI trial,In the HORIZONS-AMI trial, among high risk ptsamong high risk pts
with STEMI undergoing primary PCI, randomizationwith STEMI undergoing primary PCI, randomization
to bivalirudin monotherapy compared to UFH + GPIto bivalirudin monotherapy compared to UFH + GPI
resulted in reduced rates of bleeding, thrombo-resulted in reduced rates of bleeding, thrombo-
cytopenia, and blood transfusions; non significantlycytopenia, and blood transfusions; non significantly
different rates of reinfarction, stent thrombosis anddifferent rates of reinfarction, stent thrombosis and
TVR; and improved survival at 30 daysTVR; and improved survival at 30 days
Whether these benefits are maintained at 1-year isWhether these benefits are maintained at 1-year is
unknownunknown
-
8/14/2019 Horizons 1Year Pharm
3/33
HHarmonizingarmonizing OOutcomes withutcomes with RRevascularevascularizizatiationon andand SStents intents in AMIAMI
3602 pts with STEMI with symptom onset 12 hours3602 pts with STEMI with symptom onset 12 hours
UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)(abciximab or eptifibatide)
Bivalirudin monotherapyBivalirudin monotherapy
( provisional GP IIb/IIIa)( provisional GP IIb/IIIa)
Aspirin, thienopyridineAspirin, thienopyridineR
1:1
Emergent angiography, followed by triage to primary PCI, CABG or medical therapyEmergent angiography, followed by triage to primary PCI, CABG or medical therapy
3006 pts eligible for stent randomization3006 pts eligible for stent randomization
R
3:1
Bare metal EXPRESS stentBare metal EXPRESS stentPaclitaxel-eluting TAXUS stentPaclitaxel-eluting TAXUS stent
Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years
-
8/14/2019 Horizons 1Year Pharm
4/33
HHarmonizingarmonizing OOutcomes withutcomes with RRevascularevascularizizatiationon andand SStents intents in AMIAMI
3602 pts with STEMI with symptom onset 12 hours3602 pts with STEMI with symptom onset 12 hours
UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)(abciximab or eptifibatide)
Bivalirudin monotherapyBivalirudin monotherapy
( provisional GP IIb/IIIa)( provisional GP IIb/IIIa)
Aspirin, thienopyridineAspirin, thienopyridineR
1:1
Pharmacology ArmPharmacology Arm
Primary and Secondary EndpointsPrimary and Secondary Endpoints
1-Year1-YearIntention to Treat PopulationIntention to Treat Population
Outcomes in the 4 randomized groupsOutcomes in the 4 randomized groups
-
8/14/2019 Horizons 1Year Pharm
5/33
Study Medications (i)Study Medications (i) Unfractionated heparinUnfractionated heparin
60 U/kg IV*; subsequent boluses titrated by nomogram60 U/kg IV*; subsequent boluses titrated by nomogramto ACT 200-250 secs; terminated at procedure endto ACT 200-250 secs; terminated at procedure end
unless prolonged antithrombin neededunless prolonged antithrombin needed
BivalirudinBivalirudin
Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titratedBolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated
to ACT; terminated at procedure end unless prolongedto ACT; terminated at procedure end unless prolonged
antithrombin needed (0.25 mg/kg/hr infusion)antithrombin needed (0.25 mg/kg/hr infusion)
Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors
Routine use in UFH arm; recommended only for giantRoutine use in UFH arm; recommended only for giant
thrombus or refractory no reflow in bivalirudin armthrombus or refractory no reflow in bivalirudin arm Abciximab or double bolus eptifibatide as perAbciximab or double bolus eptifibatide as per
investigator discretion dosing per FDA label, renalinvestigator discretion dosing per FDA label, renal
adjusted; continued for 12adjusted; continued for 12 (abcx) or 12-18(abcx) or 12-18 (eptif)(eptif)
* If pre randomization UFH administered, ACT is checked first* If pre randomization UFH administered, ACT is checked first** If pre randomization UFH administered, started 30 after last bolus** If pre randomization UFH administered, started 30 after last bolus
-
8/14/2019 Horizons 1Year Pharm
6/33
2 Primary Endpoints (at 30 Days)2 Primary Endpoints (at 30 Days)
1) Net Adverse Clinical Events1) Net Adverse Clinical Events
2) Major Bleeding (non CABG)2) Major Bleeding (non CABG)
Intracranial bleeding
intraocular bleeding
Retroperitoneal bleeding
Access site bleed requiring
intervention/surgery Hematoma 5 cm
Hgb 3g/dL with an overt source
Hgb 4g/dL w/o overt source
Reoperation for bleeding
Blood product transfusion
andand
-
8/14/2019 Horizons 1Year Pharm
7/33
2 Primary Endpoints (at 30 Days)2 Primary Endpoints (at 30 Days)
1) Net Adverse Clinical Events1) Net Adverse Clinical Events
2) Major Bleeding (non CABG)2) Major Bleeding (non CABG)
==
oror
All cause death
Reinfarction
Ischemic TVR
Stroke
Major adverseMajor adverse
cardiovascular eventscardiovascular events(major secondary endpoint)(major secondary endpoint)
-
8/14/2019 Horizons 1Year Pharm
8/33
HH
armonizingarmonizing
OO
utcomes withutcomes with
RR
evascularevascular
iziz
atiati
onon
andand
SS
tents intents in
AMIAMI
UFH + GP IIb/IIIaN=1802 BivalirudinN=1800
R
1:1
RandomizedRandomized
* Biomarkers WNL and no DS >50% by core lab determination 30 day FU only* Biomarkers WNL and no DS >50% by core lab determination 30 day FU only
1-Year FU Eligible1-Year FU Eligible
30 Day FU30 Day FU N=1791 (99.4%) N=1787 (99.3%)
N=1774 N=1771
Withdrew Withdrew
Lost to FU Lost to FU
2626
4646
2222
5353
3602 pts with STEMI3602 pts with STEMI
Not true MI* Not true MI* 2828 2929
1-Year FU1-Year FU N=1702 (95.9%) N=1696 (95.8%)
-
8/14/2019 Horizons 1Year Pharm
9/33
Baseline Characteristics (i)Baseline Characteristics (i)
UFH + GP IIb/IIIaUFH + GP IIb/IIIa
(N=1802)(N=1802)
BivalirudinBivalirudin
(N=1800)(N=1800)
Age (years)Age (years) 60.7 [52.9, 70.1]60.7 [52.9, 70.1] 59.8 [51.9, 69.5]59.8 [51.9, 69.5]
MaleMale 76.1%76.1% 77.1%77.1%
DiabetesDiabetes 17.3%17.3% 15.6%15.6%HypertensionHypertension 55.2%55.2% 51.8%51.8%
HyperlipidemiaHyperlipidemia 42.7%42.7% 43.4%43.4%
Current smokingCurrent smoking 45.0%45.0% 47.2%47.2%
Prior MIPrior MI 11.4%11.4% 10.4%10.4%
Prior PCIPrior PCI 11.0%11.0% 10.5%10.5%
Prior CABGPrior CABG 2.6%2.6% 3.3%3.3%
*P=0.04*P=0.04
**
Stone GW et al. NEJMStone GW et al. NEJM 2008;358:2218-302008;358:2218-30
-
8/14/2019 Horizons 1Year Pharm
10/33
Baseline Characteristics (ii)Baseline Characteristics (ii)
UFH + GP IIb/IIIaUFH + GP IIb/IIIa
(N=1802)(N=1802)
BivalirudinBivalirudin
(N=1800)(N=1800)
Weight (kg)Weight (kg) 80 [71, 90]80 [71, 90] 80 [71, 90]80 [71, 90]
Chest pain ER, hrsChest pain ER, hrs 2.1 [1.3, 3.9]2.1 [1.3, 3.9] 2.2 [1.3, 4.0]2.2 [1.3, 4.0]
Killip class 2-4Killip class 2-4 8.5%8.5% 8.5%8.5%Anterior MIAnterior MI 43.9%43.9% 41.2%41.2%
LVEFLVEF 50 [41, 59]50 [41, 59] 50 [45, 60]50 [45, 60]
Femoral a. accessFemoral a. access 93.6%93.6% 93.9%93.9%
Venous accessVenous access 8.4%8.4% 9.3%9.3%
Closure deviceClosure device 27.7%27.7% 28.3%28.3%
Aspiration catheterAspiration catheter 11.1%11.1% 11.9%11.9%
Stone GW et al. NEJMStone GW et al. NEJM 2008;358:2218-302008;358:2218-30
-
8/14/2019 Horizons 1Year Pharm
11/33
Study DrugsStudy Drugs
UFH + GP IIb/IIIaUFH + GP IIb/IIIa
(N=1802)(N=1802)BivalirudinBivalirudin
(N=1800)(N=1800)
UFH pre randomizationUFH pre randomization 65.6%65.6% 65.6%65.6%
Antithrombin in CCLAntithrombin in CCL
- UFH- UFH 98.9%98.9% 2.6%2.6%
- Bivalirudin- Bivalirudin 0.2%0.2% 96.9%96.9%
- Peak ACT- Peak ACT 264 [228, 320]264 [228, 320] 357 [300, 402]357 [300, 402]
GP IIb/IIIa in CCLGP IIb/IIIa in CCL 94.5%*94.5%* 7.2%*7.2%*
- Bail-out per protocol**- Bail-out per protocol** -- 4.4%4.4%
- Abciximab- Abciximab 49.9%49.9% 4.0%4.0%
- Eptifibatide- Eptifibatide 44.4%44.4% 3.1%3.1%
- Tirofiban- Tirofiban 0.2%0.2% 0.1%0.1%
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory no*97.7% and 7.5% during PCI. ** For giant thrombus or refractory noreflow after PCI. CCL = cardiac catheterization laboratoryreflow after PCI. CCL = cardiac catheterization laboratory
-
8/14/2019 Horizons 1Year Pharm
12/33
Primary Management Strategy*Primary Management Strategy*
UFH + GP IIb/IIIa Inhibitor
N=1802
Bivalirudin Monotherapy
N=1800
Primary PCI Deferred PCI CABG Medical Rx
*Primary ITT analysis includes all pts regardless of treatment*Primary ITT analysis includes all pts regardless of treatment
-
8/14/2019 Horizons 1Year Pharm
13/33
Diff =Diff = 0.0% [-1.6, 1.5]
RR = 0.99RR = 0.99 [0.76, 1.30]PPsupsup = 0.95= 0.95
Primary Endpoints at 30 Days
Diff =Diff = -3.3% [-5.0, -1.6]
RR =RR = 0.60 [0.46, 0.77]PPNINI 0.0001 0.0001
PPsupsup 0.0001 0.0001
Diff =Diff = -2.9% [-4.9, -0.8]
RR =RR = 0.76 [0.63, 0.92]PPNINI 0.0001 0.0001
PPsupsup = 0.005= 0.005
1 endpoint 1 endpoint
Stone GW et al. NEJMStone GW et al. NEJM 2008;358:2218-302008;358:2218-30
Major 2 endpoint
-
8/14/2019 Horizons 1Year Pharm
14/33
Aspirin and Thienopyridine UseAspirin and Thienopyridine Use
Antiplateletagentuse
(%)
Antiplateletagentuse
(%)
Regular* aspirin use (%)Regular* aspirin use (%) Regular* thieno. use (%)Regular* thieno. use (%)
*Taken >50% of days since last visit*Taken >50% of days since last visit
97.1%
98.1%
96.7%
97.3%
96.3%
97.0%
95.7%
96.1%
92.7%
93.7%
92.9%
93.3%
87.2%
87.8%
65.8%
68.0%
All P = NSAll P = NSAll P = NSAll P = NS
-
8/14/2019 Horizons 1Year Pharm
15/33
1-Year Net Adverse Clinical Events*1-Year Net Adverse Clinical Events*
*MACE or major bleeding (non CABG)*MACE or major bleeding (non CABG)
Number at riskNumber at risk
Bivalirudin aloneBivalirudin alone
Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa
18001800 15591559 15141514 14831483 13431343
18021802 14991499 14591459 14271427 12811281
NA
CE(%)
NA
CE(%)
00
22
44
66
88
1010
1212
1414
16161818
2020
Time in MonthsTime in Months
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
18.3%18.3%
15.7%15.7%
Diff [95%CI] =Diff [95%CI] =
-2.6% [-5.1, -0.1]-2.6% [-5.1, -0.1]
HR [95%CI] =HR [95%CI] =
0.84 [0.71,0.84 [0.71,
0.98]0.98]
P=0.03P=0.03
Bivalirudin alone (n=1800)Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)
-
8/14/2019 Horizons 1Year Pharm
16/33
Number at riskNumber at risk
Bivalirudin aloneBivalirudin alone
Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa
18001800 16211621 16011601 15861586 14481448
18021802 15441544 15321532 15151515 13681368
MajorB
leeding(%)
MajorB
leeding(%)
00
11
22
33
44
55
66
77
88
99
1010
1111
1212
Time in MonthsTime in Months
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
9.2%9.2%
5.8%5.8%Diff [95%CI] =Diff [95%CI] =
-3.4% [-5.2, -1.7]-3.4% [-5.2, -1.7]22
HR [95%CI] =HR [95%CI] =
0.61 [0.48, 0.78]0.61 [0.48, 0.78]
P
-
8/14/2019 Horizons 1Year Pharm
17/33
1-Year Bleeding Endpoints*1-Year Bleeding Endpoints*
UFH + GP IIb/IIIaUFH + GP IIb/IIIa
(N=1802)(N=1802)
BivalirudinBivalirudin
(N=1800)(N=1800)
P ValueP Value
Protocol Major, non CABG**Protocol Major, non CABG** 9.2%9.2% 5.8%5.8%
-
8/14/2019 Horizons 1Year Pharm
18/33
1-Year Major Adverse CV Events*1-Year Major Adverse CV Events*
Number at riskNumber at risk
Bivalirudin aloneBivalirudin alone
Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa
Bivalirudin alone (n=1800)Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)
18001800 16271627 15791579 15441544 13941394
18021802 16191619 15731573 15401540 13801380
MA
CE(%)
MA
CE(%)
00
11
22
33
44
5566
77
88
99
1010
1111
12121313
1414
1515
Time in MonthsTime in Months
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
11.9%11.9%11.9%11.9%
Diff [95%CI] =Diff [95%CI] =
0.0% [-2.1, 2.2]0.0% [-2.1, 2.2]
HR [95%CI] =HR [95%CI] =
1.00 [0.83, 1.21]1.00 [0.83, 1.21]
P=0.98P=0.98
*MACE = All cause death, reinfarction, ischemic TVR or stroke*MACE = All cause death, reinfarction, ischemic TVR or stroke
-
8/14/2019 Horizons 1Year Pharm
19/33
1-Year All-Cause Mortality
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
1800 1705 1684 1669 1520
1802 1678 1663 1646 1486
Mor
tality(%)
0
1
2
3
4
5
Time in Months0 1 2 3 4 5 6 7 8 9 10 11 12
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802) 4.8%
3.4%
Diff [95%CI] =
-1.5% [-2.8,-0.1]HR [95%CI] =
0.69 [0.50, 0.97]
P=0.029
3.1%
2.1%
= 1.0%
P=0.049
= 1.4%
-
8/14/2019 Horizons 1Year Pharm
20/33
1-Year Mortality:1-Year Mortality: Cardiac and Non CardiacCardiac and Non Cardiac
Number at riskNumber at risk
Bivalirudin aloneBivalirudin alone
Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa
Bivalirudin alone (n=1800)Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)
18001800 17051705 16841684 16691669 15201520
18021802 16781678 16631663 16461646 14861486
CardiacCardiac
Non CardiacNon Cardiac
Mor
tality(%)
Mor
tality(%)
00
11
22
33
44
55
Time in MonthsTime in Months00 11 22 33 44 55 66 77 88 99 1010 1111 1212
3.8%
2.1%
1.3%
1.1%
HR [95%CI] =
0.57 [0.38, 0.84]
P=0.005
2.9%
1.8%
= 1.1%
P=0.03
= 1.7%
-
8/14/2019 Horizons 1Year Pharm
21/33
1-Year Death or Reinfarction
Number at riskNumber at risk
Bivalirudin aloneBivalirudin alone
Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa
18001800 16701670 16381638 16171617 14691469
18021802 16481648 16171617 15931593 14311431
Death
orMI(%)
Death
orMI(%)
00
11
22
33
44
55
66
77
8899
1010
Time in MonthsTime in Months
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
8.5%
6.6%
HR [95%CI] =
0.77 [0.61, 0.98]0.77 [0.61, 0.98]
P=0.04
4.5%
3.8%
= 0.7%
P=0.30
= 1.9%
Bivalirudin alone (n=1800)Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)Heparin + GPIIb/IIIa (n=1802)
-
8/14/2019 Horizons 1Year Pharm
22/33
1-Year MACE Components*1-Year MACE Components*
UFH + GPIUFH + GPI
(N=1802)(N=1802)BivalirudinBivalirudin
(N=1800)(N=1800)HR [95%CI]HR [95%CI]
PP
ValueValue
DeathDeath 4.8%4.8% 3.4%3.4% 0.69 [0.50,0.97]0.69 [0.50,0.97] 0.0290.029
- Cardiac- Cardiac 3.8%3.8% 2.1%2.1% 0.57 [0.38,0.84]0.57 [0.38,0.84] 0.0050.005
- Non cardiac- Non cardiac 1.1%1.1% 1.3%1.3% 1.14 [0.62,2.11]1.14 [0.62,2.11] 0.670.67
ReinfarctionReinfarction 4.4%4.4% 3.6%3.6% 0.81 [0.58,1.14]0.81 [0.58,1.14] 0.220.22
- Q-wave- Q-wave 2.1%2.1% 2.2%2.2% 1.06 [0.67,1.67]1.06 [0.67,1.67] 0.810.81
- Non Q-wave- Non Q-wave 2.7%2.7% 1.4%1.4% 0.53 [0.32,0.86]0.53 [0.32,0.86] 0.010.01
Death or reinfarctionDeath or reinfarction 8.5%8.5% 6.6%6.6% 0.77 [0.61,0.98]0.77 [0.61,0.98] 0.040.04
Ischemic TVRIschemic TVR 5.9%5.9% 7.2%7.2% 1.23 [0.94,1.60]1.23 [0.94,1.60] 0.120.12- Ischemic TLR- Ischemic TLR 4.5%4.5% 6.0%6.0% 1.34 [1.00,1.80]1.34 [1.00,1.80] 0.0510.051
- Ischemic remote TVR- Ischemic remote TVR 2.0%2.0% 2.3%2.3% 1.13 [0.71,1.79]1.13 [0.71,1.79] 0.600.60
StrokeStroke 1.2%1.2% 1.1%1.1% 1.00 [0.54,1.85]1.00 [0.54,1.85] 0.990.99
*All Kaplan-Meier estimates, CEC adjudicated*All Kaplan-Meier estimates, CEC adjudicated
-
8/14/2019 Horizons 1Year Pharm
23/33
Adverse Events Between 30 Days and 1-YearAdverse Events Between 30 Days and 1-Year
UFH + GPIUFH + GPI
(N=1802)(N=1802)
BivalirudinBivalirudin
(N=1800)(N=1800)
P ValueP Value
DeathDeath 1.8%1.8% 1.4%1.4% 0.310.31
- Cardiac- Cardiac 0.9%0.9% 0.4%0.4% 0.0460.046
- Non cardiac- Non cardiac 0.9%0.9% 1.0%1.0% 0.750.75
ReinfarctionReinfarction 2.8%2.8% 1.7%1.7% 0.040.04
Death or reinfarctionDeath or reinfarction 4.4%4.4% 3.0%3.0% 0.020.02
Ischemic TVRIschemic TVR 4.3%4.3% 4.7%4.7% 0.570.57
StrokeStroke 0.5%0.5% 0.4%0.4% 0.770.77
MACEMACE 7.3%7.3% 6.8%6.8% 0.520.52
Major bleeding (non CABG)Major bleeding (non CABG) 0.7%0.7% 0.8%0.8% 0.710.71
NACENACE 7.8%7.8% 7.3%7.3% 0.520.52
*Kaplan-Meier estimates, landmark analysis, CEC adjudicated*Kaplan-Meier estimates, landmark analysis, CEC adjudicated
-
8/14/2019 Horizons 1Year Pharm
24/33
1-Year Stent Thrombosis (ARC Definite/Probable)1-Year Stent Thrombosis (ARC Definite/Probable)
Number at riskNumber at risk
Bivalirudin aloneBivalirudin alone
Heparin+GPIIb/IIIaHeparin+GPIIb/IIIa
16111611 15251525 15041504 14861486 13561356
15911591 14951495 14751475 14571457 13151315
StentTh
rombosis(%)
StentTh
rombosis(%)
00
11
22
33
44
55
Time in MonthsTime in Months00 11 22 33 44 55 66 77 88 99 1010 1111 1212
Bivalirudin alone (n=1611)Bivalirudin alone (n=1611)
Heparin + GPIIb/IIIa (n=1591)Heparin + GPIIb/IIIa (n=1591)
3.5%3.2%
HR [95%CI] =1.11 [0.76, 1.63]
P=0.59
2.7%
2.2%
= 0.5%
P=0.31
= 0.3%
-
8/14/2019 Horizons 1Year Pharm
25/33
1-Year Stent Thrombosis* (N=3,202)1-Year Stent Thrombosis* (N=3,202)
UFH + GPIUFH + GPI
(N=1591)(N=1591)BivalirudinBivalirudin
(N=1611)(N=1611)PP
ValueValue
ARC definite or probable, 24 hrsARC definite or probable, 24 hrs 0.3%0.3% 1.5%1.5% 0.00020.0002
- definite, 24 hours- definite, 24 hours 0.2%0.2% 1.4%1.4% 1 - 30d 1.9%1.9% 1.3%1.3% 0.140.14
- definite, >1 day - 30 days- definite, >1 day - 30 days 1.3%1.3% 1.1%1.1% 0.600.60
- probable, >1 day - 30 days- probable, >1 day - 30 days 0.6%0.6% 0.2%0.2% 0.0490.049
ARC definite or probable, >30d 1yARC definite or probable, >30d 1y 1.1%1.1% 0.9%0.9% 0.530.53
- definite, >30 days 1-year- definite, >30 days 1-year 1.0%1.0% 0.9%0.9% 0.650.65
- probable, >30 days 1-year- probable, >30 days 1-year 0.1%0.1% 0.1%0.1% 0.550.55
ARC definite or probable, 1-yearARC definite or probable, 1-year 3.2%3.2% 3.5%3.5% 0.590.59
- definite, 1-year- definite, 1-year 2.4%2.4% 3.2%3.2% 0.150.15
- probable, 1-year- probable, 1-year 0.8%0.8% 0.3%0.3% 0.060.06
*All Kaplan-Meier estimates except 24 hours; all CEC adjudicated*All Kaplan-Meier estimates except 24 hours; all CEC adjudicated
-
8/14/2019 Horizons 1Year Pharm
26/33
HHarmonizingarmonizing OOutcomes withutcomes with RRevascularevascularizizatiationon andand SStents intents in AMIAMI
R
1:1
3602 pts with STEMI3602 pts with STEMI
Stent rand.
eligible
UFH + GP IIb/IIIaN=1802
N=1479
TAXUS
N=1111
EXPRESS
N=368
BivalirudinN=1800
N=1527
TAXUS
N=1146
EXPRESS
N=381
R3:1
R3:1
Stratified by 1st rand.
-
8/14/2019 Horizons 1Year Pharm
27/33
Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization
30 Day Pharmacology Endpoints (N=3006)30 Day Pharmacology Endpoints (N=3006)
Kaplan-Meier estimatesKaplan-Meier estimates
UFH + GPIUFH + GPI
(N=1479)(N=1479)
BivalirudinBivalirudin
(N=1527)(N=1527) HR [95%CI]HR [95%CI] PPintint
NACE, all*NACE, all* 11.3%11.3% 8.7%8.7% 0.76 [0.60,0.95]0.76 [0.60,0.95] --
- TAXUS subgroup- TAXUS subgroup 11.5%11.5% 9.1%9.1% 0.78 [0.60,1.01]0.78 [0.60,1.01]0.950.95
- EXPRESS subgroup- EXPRESS subgroup10.6%10.6% 7.4%7.4% 0.69 [0.42,1.11]0.69 [0.42,1.11]
Major bleeding, all**Major bleeding, all** 8.4%8.4% 5.1%5.1% 0.59 [0.44,0.78]0.59 [0.44,0.78] --
- TAXUS subgroup- TAXUS subgroup 8.9%8.9% 5.4%5.4% 0.59 [0.43,0.81]0.59 [0.43,0.81]1.01.0
- EXPRESS subgroup- EXPRESS subgroup 7.1%7.1% 4.2%4.2% 0.58 [0.31,1.09]0.58 [0.31,1.09]
MACE, all***MACE, all*** 4.7%4.7% 4.9%4.9% 1.05 [0.75,1.45]1.05 [0.75,1.45] --
- TAXUS subgroup- TAXUS subgroup 4.6%4.6% 5.1%5.1% 1.11 [0.76,1.62]1.11 [0.76,1.62]0.890.89
- EXPRESS subgroup- EXPRESS subgroup 4.9%4.9% 4.2%4.2% 0.86 [0.44,1.69]0.86 [0.44,1.69]
*MACE or major bleeding; **Protocol defined (non CABG);*MACE or major bleeding; **Protocol defined (non CABG);***Death, reinfarction, stroke or ischemic TVR***Death, reinfarction, stroke or ischemic TVR
S
-
8/14/2019 Horizons 1Year Pharm
28/33
Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization
1-Year Stent Endpoints (N=3006)1-Year Stent Endpoints (N=3006)
Kaplan-Meier estimatesKaplan-Meier estimates
TAXUSTAXUS
(N=2257)(N=2257)
EXPRESSEXPRESS
(N=749)(N=749) HR [95%CI]HR [95%CI] PPintint
Ischemic TLR, allIschemic TLR, all 4.5%4.5% 7.5%7.5% 0.59 [0.43,0.83]0.59 [0.43,0.83] --
- UFH + GPI subgroup- UFH + GPI subgroup 3.3%3.3% 7.9%7.9% 0.42 [0.25,0.68]0.42 [0.25,0.68]0.170.17
- Bivalirudin subgroup- Bivalirudin subgroup5.6%5.6% 7.1%7.1% 0.78 [0.50,1.24]0.78 [0.50,1.24]
Safety MACE, all*Safety MACE, all* 8.1%8.1% 8.0%8.0% 1.02 [0.76, 1.36]1.02 [0.76, 1.36] --
- UFH + GPI subgroup- UFH + GPI subgroup 8.2%8.2% 8.8%8.8% 0.92 [0.66,1.27]0.92 [0.66,1.27]0.890.89
- Bivalirudin subgroup- Bivalirudin subgroup 8.0%8.0% 7.2%7.2% 1.17 [0.83,1.64]1.17 [0.83,1.64]
Binary restenosis, all**Binary restenosis, all** 10.0%10.0% 22.9%22.9% 0.44 [0.33, 0.57]0.44 [0.33, 0.57] --
- UFH + GPI subgroup- UFH + GPI subgroup 10.9%10.9% 19.2%19.2% 0.57 [0.38,0.84]0.57 [0.38,0.84]0.180.18
- Bivalirudin subgroup- Bivalirudin subgroup 9.2%9.2% 26.7%26.7% 0.34 [0.24,0.49]0.34 [0.24,0.49]
*Death, reinfarction, stroke or stent thrombosis*Death, reinfarction, stroke or stent thrombosis**1081 lesions in the TAXUS group, 332 in the EXPRESS group**1081 lesions in the TAXUS group, 332 in the EXPRESS group
-
8/14/2019 Horizons 1Year Pharm
29/33
1-Year Mortality (All-Cause)1-Year Mortality (All-Cause)
Heparin + GPI / TAXUS (n=1111)Heparin + GPI / TAXUS (n=1111)
Heparin + GPI / EXPRESS (n=368)Heparin + GPI / EXPRESS (n=368)
Bivalirudin / TAXUS (n=1146)Bivalirudin / TAXUS (n=1146)Bivalirudin / EXPRESS (n=381)Bivalirudin / EXPRESS (n=381)
4.0%4.0%
3.0%3.0%
PPintint = 0.75= 0.75
4.6%4.6%
2.6%2.6%
Mortality(%)
Mortality(%)
00
11
22
33
44
55
Time in MonthsTime in Months
00 11 22 33 44 55 66 77 88 99 1010 1111 1212
-
8/14/2019 Horizons 1Year Pharm
30/33
LimitationsLimitations
Open label designOpen label design
Potential bias was mitigated by highPotential bias was mitigated by high
protocol procedure compliance and useprotocol procedure compliance and use
of blinded clinical event adjudicationof blinded clinical event adjudication
committees and core laboratoriescommittees and core laboratories
Underpowered for low frequency safetyUnderpowered for low frequency safety
endpoints and subgroup interactionsendpoints and subgroup interactions
All such observations should beAll such observations should be
considered hypothesis-generatingconsidered hypothesis-generating
-
8/14/2019 Horizons 1Year Pharm
31/33
ConclusionsConclusions
In this large scale, prospective, randomizedIn this large scale, prospective, randomized
trial of pts with STEMI undergoing a primarytrial of pts with STEMI undergoing a primary
PCI management strategy, bivalirudinPCI management strategy, bivalirudin
monotherapy compared to UFH plus themonotherapy compared to UFH plus the
routine use of GP IIb/IIIa inhibitors resulted in:routine use of GP IIb/IIIa inhibitors resulted in:
A significant 16% reduction in the 1-year rateA significant 16% reduction in the 1-year rate
of composite net adverse clinical eventsof composite net adverse clinical events
A significant 39% reduction in the 1-year rateA significant 39% reduction in the 1-year rate
of major bleedingof major bleeding
-
8/14/2019 Horizons 1Year Pharm
32/33
ConclusionsConclusions
In this large scale, prospective, randomizedIn this large scale, prospective, randomized
trial of pts with STEMI undergoing a primarytrial of pts with STEMI undergoing a primary
PCI management strategy, bivalirudinPCI management strategy, bivalirudin
monotherapy compared to UFH plus themonotherapy compared to UFH plus the
routine use of GP IIb/IIIa inhibitors resulted in:routine use of GP IIb/IIIa inhibitors resulted in:
Significant 31% and 43% reductions in theSignificant 31% and 43% reductions in the
1-year rates of all-cause and cardiac1-year rates of all-cause and cardiac
mortality (absolute 1.4% and 1.7% reductions),mortality (absolute 1.4% and 1.7% reductions),with non significantly different rates ofwith non significantly different rates of
reinfarction, stent thrombosis, stroke and TVRreinfarction, stent thrombosis, stroke and TVR
at 1-yearat 1-year
-
8/14/2019 Horizons 1Year Pharm
33/33
Clinical ImplicationsClinical Implications
HORIZONS has demonstrated that theHORIZONS has demonstrated that the
prevention of hemorrhagic complicationsprevention of hemorrhagic complications
after primary PCI in STEMI results inafter primary PCI in STEMI results in
improved early and late survivalimproved early and late survival
Optimal drug selection and techniqueOptimal drug selection and technique
to minimize bleeding are essential toto minimize bleeding are essential to
enhance outcomes for pts undergoingenhance outcomes for pts undergoing
interventional therapiesinterventional therapies