Transcript The Detrimental Impact of Chronic Renal Insufficiency

A Prospective, Multicenter Randomized
Trial of Heparin Plus Glycoprotein IIb/IIIa
Inhibitors vs. Bivalirudin, and Drug-eluting
vs. Bare Metal Stents in ST-Segment
Elevation Myocardial Infarction: Final
Report from the HORIZONS-AMI Trial
Gregg W. Stone MD
For the HORIZONS-AMI Investigators
Disclosures

Gregg W. Stone MD
– Advisory Board for and honoraria from Boston
Scientific and Abbott Vascular
– Consultant to the The Medicines Company
Background

At 1-year in the 2x2 factorial prospective,
randomized HORIZONS-AMI trial:
– Bivalirudin alone compared to heparin plus GPIIb/IIIa
inhibitors resulted in comparable rates of MI and
stent thrombosis, with significantly reduced rates of
major bleeding and mortality (all-cause and cardiac)
– TAXUS PES compared to EXPRESS BMS reduced
clinical and angiographic restenosis, with comparable
rates of death, reinfarction and stent thrombosis

Whether these findings are sustained with longterm follow-up has not been reported
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI with symptom onset ≤12 hours
Aspirin, thienopyridine
R
1:1
UFH + GP IIb/IIIa inhibitor
(abciximab or eptifibatide)
Bivalirudin monotherapy
(± provisional GP IIb/IIIa)
Emergent angiography, followed by triage to…
CABG – Primary PCI – Medical Rx
3006 pts eligible for stent randomization
R
3:1
Paclitaxel-eluting TAXUS stent
Bare metal EXPRESS stent
Clinical FU at 30 days, 6 months, 1 year, and then
yearly through 5 years; angio FU at 13 months
Harmonizing Outcomes with Revascularization and Stents in AMI
3602 pts with STEMI
R
1:1
Randomized
UFH + GP IIb/IIIa
N=1802
30
1-Year FU Eligible
1-Year FU
3-Year FU
• • • Not true MI* • • •
N=1772
Bivalirudin
N=1800
29
N=1771
26
• • • Withdrew • • •
22
13
• • • Lost to FU • • •
19
N=1733 (97.8%)
N=1730 (97.7%)
17
• • • Withdrew • • •
18
90
• • • Lost to FU • • •
78
N=1626 (91.7%)
* Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)
N=1634 (92.3%)
Pharmacology Randomization:
Aspirin and Thienopyridine Use
Regular* aspirin use (%)
98.1%
97.3%
Heparin + GPIIb/IIIa (n=1802)
Bivalirudin alone (n=1800)
97.0%
94.9% 100
93.7%
94.0%
92.7%
96.2%
Antiplatelet agent use (%)
100
97.1%
96.7%
Regular* thieno. use (%)
96.3%
95.7%
95.4%
95.3%
80
80
60
60
93.3%
87.7%
92.9%
87.1%
67.7%
65.6%
All P = NS
40
35.5%
All P = NS
40
27.4%
32.7%
20
20
0
0
D/C
30 D
6 Mo
1 Yr
*Taken >50% of days since last visit
2 Yr
3 Yr
25.6%
D/C
30 D
6 Mo
1 Yr
2 Yr
3 Yr
Three-Year Major Bleeding (non-CABG)*
Bivalirudin alone (n=1800)
Major Bleeding (%)
12
Heparin + GPIIb/IIIa (n=1802)
10.5%
10
9.4%
8
6.9%
6
6.0%
4
3-yr HR [95%CI]=
0.64 [0.51, 0.80]
P<0.001
1-yr HR [95%CI]=
0.62 [0.49, 0.79]
P<0.001
2
0
0
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
3
6
9
12
15
18
21
24
27
30
33
36
Months
1800
1802
1601
1534
1572
1509
1544
1465
1523
1442
1485
1402
* Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery,
hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding;
or blood product transfusion
1039
957
Three-Year All-Cause Mortality
Bivalirudin alone (n=1800)
All-Cause Mortality (%)
10
Heparin + GPIIb/IIIa (n=1802)
9
7.7%
8
7
6
5
3-yr HR [95%CI]=
0.75 [0.58, 0.97]
P=0.03
4
3
3.4%
2
1-yr HR [95%CI]=
0.71 [0.51, 0.98]
P=0.04
1
0
0
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
5.9%
4.8%
3
6
9
12
15
18
21
24
27
30
33
36
Months
1800
1802
1689
1670
1660
1643
1633
1593
1611
1568
1574
1525
1098
1043
Time in Months
'
Time in Months
3-Year Mortality: Cardiac and Non Cardiac
Heparin + GPIIb/IIIa (n=1802)
1-yr HR [95%CI]=
0.57 [0.38, 0.84]
5
3-yr HR [95%CI]=
0.56 [0.40, 0.80]
P=0.001
5.1%
P=0.004
4
3.8%
3
2.9%
2
2.1%
1
6
Non-Cardiac Mortality (%)
Cardiac Mortality (%)
6
Bivalirudin alone (n=1800)
3-yr HR [95%CI]=
1.11 [0.74, 1.65]
P=0.62
5
4
1-yr HR [95%CI]=
1.20 [0.65, 2.20]
P=0.56
3
3.1%
2.8%
2
1.3%
1
1.1%
0
0
0
3
6
9
12
15
18
21 24
27 30
33 36
Months
Number at risk
0
3
6
9
12
15
18 21 24
27
30
33
36
Months
Number at risk
Bival
1800
1689
1660
1633
1611
1574
1098
Bival
1800
1689
1660
1633
1611
1574
1098
H + GPI
1802
1670
1643
1593
1568
1525
1043
H + GPI
1802
1670
1643
1593
1568
1525
1043
Three-Year Reinfarction
Bivalirudin alone (n=1800)
10
Heparin + GPIIb/IIIa (n=1802)
Reinfarction (%)
9
8.2%
8
1-yr HR [95%CI]=
0.81 [0.58, 1.14]
P=0.22
7
6
6.2%
5
4.4%
4
3-yr HR [95%CI]=
0.76 [0.59, 0.92]
P=0.04
3
3.6%
2
1
0
0
Number at risk
Bivalirudin alone
Heparin+GPIIb/IIIa
3
6
9
12
15
18
21
24
27
30
33
36
Months
1800
1802
1643
1623
1605
1581
1560
1513
1536
1474
1494
1425
1032
965
Three-Year MACE Components*
UFH + GPI
(N=1802)
Bivalirudin
(N=1800)
HR [95%CI]
P
Value
7.7%
5.9%
0.75 [0.58,0.97]
0.03
- Cardiac
5.1%
2.9%
0.56 [0.40,0.80]
0.001
- Non cardiac
2.8%
3.1%
1.11 [0.74,1.65]
0.62
Reinfarction
8.2%
6.2%
0.76 [0.59,0.99]
0.04
- Q-wave
3.8%
3.4%
0.91 [0.64,1.30]
0.61
- Non Q-wave
4.9%
3.2%
0.63 [0.45,0.90]
0.009
Death or reinfarction
14.5%
11.3%
0.77 [0.64,0.92]
0.005
Ischemic TVR
12.1%
14.2%
1.19 [0.99,1.44]
0.06
- Ischemic TLR
9.7%
11.3%
1.18 [0.96,1.46]
0.11
- Ischemic remote TVR
4.1%
5.2%
1.25 [0.91,1.71]
0.17
2.0%
1.7%
0.84 [0.51,1.38]
0.50
Death
Stroke
*Kaplan-Meier estimates, CEC adjudicated
Adverse Events Between 30 Days and 3-Years
UFH + GPI Bivalirudin
P Value
(N=1802) (N=1800)
Death
4.8%
3.9%
0.22
- Cardiac
2.1%
1.1%
0.01
- Non cardiac
2.6%
2.8%
0.67
Reinfarction
6.5%
4.4%
0.007
Death or reinfarction
10.6%
7.8%
0.005
Ischemic TVR
10.6%
11.7%
0.31
Stroke
1.4%
1.0%
0.29
MACE
17.8%
17.3%
0.65
Major bleeding (non CABG)
1.9%
2.1%
0.67
NACE
18.7%
18.2%
0.73
*Kaplan-Meier estimates, landmark analysis, CEC adjudicated
Stent Thrombosis (%)
Three-Year Stent Thrombosis
(ARC Definite/Probable)
Bivalirudin alone (n=1611)
6
Heparin + GPIIb/IIIa (n=1591)
5.1%
4.5%
5
3.5%
4
HR [95%CI]=
0.89 [0.65, 1.23]
p=0.49
3
3.0%
2
HR [95%CI]=
1.16 [0.79, 1.71]
p=0.45
1
0
0
Number at risk
Bivalirudin
1611
Heparin+GPIIb/IIIa 1591
3
6
9
12
15
18
21
24
27
30
33
36
Months
1509
1484
1478
1456
1453
1401
1432
1373
1398
1335
971
906
Three-Year Stent Thrombosis* (N=3,202)
UFH + GPI Bivalirudin
(N=1591) (N=1611)
ARC definite or probable, ≤24 hours
P
Value
0.3%
1.5%
<0.001
- definite, ≤24 hours
0.2%
1.5%
<0.001
- probable, ≤24 hours
0.1%
0.0%
0.32
4.8%
3.1%
0.01
- definite, >24 hours – 3 years
4.0%
2.8%
0.08
- probable, >24 hours – 3 years
0.9%
0.3%
0.03
5.1%
4.5%
0.49
- definite, ≤3 years
4.1%
4.2%
0.87
- probable, ≤3 years
1.0%
0.3%
0.02
ARC definite or probable, >24h – 3y
ARC definite or probable, ≤3 years
*All Kaplan-Meier estimates; all CEC adjudicated
Harmonizing Outcomes with Revascularization and Stents in AMI
Primary Medical Rx
193
Primary CABG
62
Deferred PCI
2
Index PCI, not eligible
- PTCA only
119
- Stented
220
3602 pts with STEMI
Bivalirudin (n=1800)
R
3:1
TAXUS DES
N=2257
EXPRESS BMS
N=749
18
• • • Withdrew • • •
7
16
• • • Lost to FU • • •
13
1 year FU N=2225 (98.6%)
13 month angiographic FU
UFH + GPI (n=1802)
3006 pts eligible for stent rand.
93.1% of all stented
pts were randomized
Randomized
R
1:1
942
N=730 (97.5%)
23
• • • Withdrew • • •
8
97
• • • Lost to FU • • •
34
3 year FU N=2103 (93.2%)
307
N=687 (91.7%)
Stent Randomization:
Aspirin and Thienopyridine Use
Regular* aspirin use (%)
Regular* thieno. use (%)
TAXUS DES (n=2257)
99.1%
98.3%
98.3%
97.5%
97.5%
95.8%
97.1%
96.3%
95.7%
Antiplatelet agent use (%)
100
98.6%
98.5%
97.4%
EXPRESS BMS (n=749)
99.4%
98.7%
94.6%
100
98.9%
97.8%
80
80
72.8%
87.5%
P<0.001
60
60
63.6%
All P=NS
P<0.001
36.7%
40
40
28.3%
30.5%
20
20
P=0.004
22.5%
P=0.003
0
0
D/C
30 D
6 Mo
1 Yr
*Taken >50% of days since last visit
2 Yr
3 Yr
D/C
30 D
6 Mo
1 Yr
2 Yr
3 Yr
Primary Efficacy Endpoint: Ischemic TLR
Ischemic TLR (%)
18
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
16
15.1%
14
12
1-yr HR [95%CI]=
0.61 [0.44, 0.85]
P=0.003
10
9.4%
8
7.4%
6
4
3-yr HR [95%CI]=
0.60 [0.48, 0.76]
P<0.001
4.6%
2
0
0
Number at risk
TAXUS DES
EXPRESS BMS
3
6
9
12
15
18
21
24
27
30
33
36
Months
2257
749
2104
676
2042
655
1942
598
1902
587
1846
567
1277
372
Primary Efficacy Endpoint: Ischemic TLR
No routine angiographic FU
Routine angiographic FU
TAXUS DES (n=911)
EXPRESS BMS (n=293)
TAXUS DES (n=1346)
EXPRESS BMS (n=456)
24
24
20
Ischemic TLR (%)
22
1-yr HR [95%CI]=
0.58 [0.32, 1.04]
18
20
18.3%
P=0.06
16
14
12
10.3%
10
8
3-yr HR [95%CI]=
0.53 [0.38, 0.75]
P=0.001
6
4
2
Ischemic TLR (%)
22
18
14
1-yr HR [95%CI]=
0.64 [0.43, 0.95]
12
P=0.02
16
12.7%
10
8.7%
8
6
3-yr HR [95%CI]=
0.67 [0.48, 0.93]
P=0.01
4
2
0
0
0
3
6
9
12
15
18 21
24
27
30
33
36
Months
Number at risk
0
3
6
9
12
15
18 21
24
27 30
33 36
Months
Number at risk
PES
911
896
878
830
812
795
596
PES
1346
1208
1164
1112
1090
1051
681
BMS
293
282
274
237
234
229
157
BMS
456
394
381
361
353
338
215
Primary Safety Endpoint: Safety MACE*
Safety MACE (%)
16
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
14
13.6%
12.9%
12
10
3-yr HR [95%CI]=
1.05 [0.84, 1.33]
P=0.66
8.1%
8
6
8.0%
4
1-yr HR [95%CI]=
1.02 [0.76, 1.36]
P=0.92
2
0
0
Number at risk
TAXUS DES
EXPRESS BMS
3
6
9
12
15
18
21
24
27
30
33
36
Months
2257
749
2094
684
2037
669
1971
648
1928
634
* Safety MACE = death, reinfarction, stroke, or stent thrombosis
1875
615
1289
412
Three-Year Composite Safety Endpoints*
TAXUS
(N=2257)
EXPRESS
(N=749)
HR [95%CI]
P
Value
Safety MACE
13.6%
12.9%
1.05 [0.84,1.33]
0.66
Death, all-cause
5.6%
6.6%
0.84 [0.60,1.17]
0.31
- Cardiac
3.2%
3.8%
0.84 [0.54,1.30]
0.42
- Non cardiac
2.4%
2.9%
0.85 [0.51,1.42]
0.53
Reinfarction
7.0%
6.6%
1.05 [0.76,1.46]
0.77
- Q-wave
3.5%
2.8%
1.24 [0.76,2.03]
0.39
- Non Q-wave
4.0%
3.8%
1.02 [0.66,1.57]
0.94
Stent thrombosis
4.8%
4.3%
1.10 [0.74,1.65]
0.63
- ARC definite
4.2%
3.7%
1.12 [0.73,1.72]
0.61
- ARC probable
0.6%
0.6%
1.00 [0.32,3.09]
0.99
1.6%
1.4%
1.15 [0.57,2.32]
0.70
Stroke
*Kaplan-Meier estimates
Three-Year Stent Thrombosis
(ARC Definite or Probable)
Stent Thrombosis (%)
6
TAXUS DES (n=2238)
EXPRESS BMS (n=744)
5
4.8%
4.3%
4
3.4%
3
3-yr HR [95%CI]=
1.10 [0.74, 1.65]
P=0.63
3.1%
2
1-yr HR [95%CI]=
0.92 [0.58, 1.45]
P=0.72
1
0
0
Number at risk
TAXUS DES
EXPRESS BMS
3
6
9
12
15
18
21
24
27
30
33
36
Months
2238
744
2108
695
2066
683
2013
664
1980
654
1932
637
1341
425
Three-Year Reinfarction
10
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
Reinfarction (%)
9
8
7.0%
6.6%
7
6
4.5%
5
3
3.7%
2
1-yr HR [95%CI]=
0.81 [0.54, 1.21]
P=0.31
1
0
0
Number at risk
TAXUS DES
EXPRESS BMS
3-yr HR [95%CI]=
1.05 [0.76, 1.46]
P=0.77
4
3
6
9
12
15
18
21
24
27
30
33
36
Months
2257
749
2118
690
2066
676
2002
654
1961
643
1910
624
1316
419
Three-Year All-Cause Mortality
All-Cause Mortality (%)
8
TAXUS DES (n=2257)
EXPRESS BMS (n=749)
7
6.6%
6
5.6%
5
4
3.5%
3
3-yr HR [95%CI]=
0.84 [0.60, 1.17]
P=0.31
3.5%
2
1-yr HR [95%CI]=
0.99 [0.64, 1.55]
P=0.97
1
0
0
Number at risk
TAXUS DES
EXPRESS BMS
3
6
9
12
15
18
21
24
27
30
33
36
Months
2257
749
2170
713
2138
702
2097
683
2072
674
2026
657
1409
443
Three-Year Mortality (All-Cause)
All-Cause Mortality (%)
'
Heparin + GPI / TAXUS (n=1111)
Heparin + GPI / EXPRESS (n=368)
Bivalirudin / TAXUS (n=1146)
Bivalirudin / EXPRESS (n=381)
8
7
7.3%
6.3%
6.0%
7
5
4.9%
4
3
Pint = 0.89
2
1
0
0
3
6
9
12
15
18
21
Months
24
27
30
33
36
Conclusions: Pharmacology Randomization

In this large-scale, prospective, randomized trial of pts
with STEMI undergoing primary PCI, the initial treatment
with bivalirudin alone compared to heparin plus
GPIIb/IIIa inhibitors at 3 years resulted in:
– A significant 36% reduction in major bleeding and
a significant 24% reduction in reinfarction, with non
significantly different rates of stent thrombosis, TVR
and stroke
– A significant 44% reduction in cardiac mortality and
a 25% reduction in all-cause mortality, the latter
representing 18 lives saved per 1000 patients
treated with bivalirudin (NNT = 56 to save 1 life)
Conclusions: Stent Randomization

Among pts with STEMI undergoing primary PCI,
at 3 years the implantation of TAXUS EXPRESS
PES compared to EXPRESS BMS resulted in:
– A significant 40% reduction in ischemic TLR,
with no evidence of late catch-up
– In pts without routine angiographic follow-up,
the absolute reduction in TLR was 4.0% at 3
years (NNT = 25)
– Non significantly different rates of all-cause and
cardiac mortality, reinfarction and stent
thrombosis