bivalirudin: optimising antithrombotic therapy in acute coronary … · 2016-12-09 ·...
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Bivalirudin: Optimising
Antithrombotic Therapy in
Acute Coronary Syndromes
Jonathan Briers MB; ChB
Medical Director – Northern Europe
The Medicines Company
PCI – Therapeutic targets in
adjunctive pharmacotherapy
Limit
ischaemic
complications
Minimize
bleeding
Re-establish flow
The critical roles of thrombin
ADP
+
TXA2
Neutrophils Monocytes
Activated
platelets
Endothelial cells
Activated
platelets
Resting
platelets
Monocyte
Resting
platelets
II Tenase complex
Thrombin
Prothrombin
Prothrombinase
complex
TF
Activated
platelets
Fibrin
Croce K et al. Curr Opin Hematol. 2007;14:55–61; Coughlin SR. Nature. 2000;407:258–64; Mann KG. Chest. 2003;124:4S–10S; Monroe DM et al. Arterioscler Thromb Vasc Biol. 2002;22:1381–89.
THROMBIN
ADP: adenosine diphosphate;
TxA2: thromboxane A2.
Bivalirudin mechanism of action
● Bivalirudin exhibits direct and reversible binding to thrombin (both circulating and clot bound thrombin)
Maraganore J et al Biochemistry 1990;30:7095-101
(Gly)4
D-Phe-Pro-Arg-Pro
(active-site-binding portion)
C-terminal dodecapeptide
(Substrate recognition / Exosite 1-binding portion)
Thrombin
Bivalirudin binds to active site and
substrate recognition site of thrombin
Bivalirudin is cleaved by thrombin; allowing
thrombin to resume its physiological function
NICE STEMI
● Recommendation (July 2011)
“Bivalirudin in combination with aspirin and clopidogrel is recommended for the
treatment of adults with ST-segment-elevation myocardial infarction undergoing
primary percutaneous coronary intervention.”
“In the base-case analysis the bivalirudin strategy dominated the heparin plus
glycoprotein IIb/IIIa inhibitor strategy because it was cheaper and more
effective… sensitivity analysis presented for the base-case 1-year analysis
showed that the bivalirudin strategy was dominant (that is, it was cost-saving
and showed a QALY gain).”
http://www.nice.org.uk/guidance/TA230
Guidelines for the management of
acute myocardial infarction in
patients presenting with
ST segment elevation
The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC)
Steg G et al Eur Heart J. 2012;33:2569-619.
ESC 2012 Guidelines: Management of
STEMI
Class Level
An injectable anticoagulant must be used in primary PCI I C
Bivalirudin (with use of GP IIb/ IIIa blocker restricted to bail out) is recommended over unfractionated
heparin and a GP IIb/ IIIa blocker I B
Enoxaparin (with or without routine GP IIb/ IIIa blocker) may be preferred over unfractionated heparin IIb B
Unfractionated heparin with or without routine GP IIb/ IIIa blocker must be used in patients not receiving
bivalirudin or enoxaparin I C
Fondaparinux is not recommended for primary PCI III B
The use of fibrinolysis before planned primary PCI is not recommended III A
● Peri-procedural antithrombotic medication in primary PCI – Anticoagulant Therapy
Steg G et al Eur Heart J. 2012;33:2569-619.
30-day Clinical Outcomes
P=0.95 P<0.001 P=0.005
30-d
ay e
vent ra
tes (
%)
*93% of bivalirudin patients received monotherapy without provisional GP IIb/IIIa.
MACE=all-cause death, reinfarction, ischemic TVR, or stroke; NACE=net adverse clinical events=major bleeding + MACE
Stone GW. NEJM 2008;358:2218-30.
12.1
8.3
5.5
9.2
4.9 5.4
0
5
10
15
20
NACE Non-CABG major bleeding MACE
Heparin + GP IIb/ IIIa inhibitor (n = 1,802) Bivalirudin (n= 1800)*
30-day MACE Components†
Stone GW. New Engl J Med. 2008;358:2218–30.
* 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa inhibitor. † Adjudicated by blinded CEC.
Bivalirudin
(n=1,800)*
UFH +
GP IIb/IIIa inhibitor
(n=1,802) P-value
Mortality† 2.1% 3.1% 0.047
- Cardiac 1.8% 2.9% 0.03
- Non-cardiac 0.3% 0.2% 0.75
Reinfarction† 1.8% 1.8% 0.90
- Q-wave 1.4% 1.2% 0.66
- Non-Q-wave 0.4% 0.7% 0.37
Ischaemic TVR† 2.6% 1.9% 0.18
Stroke† 0.7% 0.6% 0.68
Cardiac Mortality
30 days to 3 years*
'
Bivalirudin (n=1800) Heparin + GPIIb/IIIa (n=1802)
Stone GW et al NEJM 2008;358:2218-30; Mehran R et al Lancet. 2009;374:1149-59; Stone GW et al. Lancet 2011;377:2193-204
Card
iac M
ort
alit
y (
%)
3-yr† HR [95%CI]=
0.56 [0.40, 0.80]
P=0.001
2.9%
5.1% 1-yr† HR [95%CI]=
0.57 [0.38, 0.84]
P=0.005
0 12 15 18 21 24 27 30 33 36
Months
3 6 9
0
1
6
5
4
3
2
3.8%
2.1%
30-d† HR [95% CI]
0.62; [0.40,0.96]
P = 0.03
1.8%
2.9%
*All cause mortality at 3 years was also consistently lower with bivalirudin (5·9% vs 7·7%),
HR 0·75 [0·58–0·97]; p=0·03 †These timepoints were prespecified analyses
12
0
4
6
8
10
2
0
12 15 18 21 24 27 30 33 36
3-yr HR [95%CI]=
0.64 [0.51, 0.80]
P<0.001
6.9%
10.5%
Majo
r B
leedin
g,
non
-CA
BG
(%
)
Months
3 6 9
Δ=64
major bleeds
3-Year Major Bleeding*
* 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
Stone GW et al. Lancet 2011;377:2193-204
Bivalirudin (n=1800) Heparin + GPIIb/IIIa (n=1802)
Day 0–1 after MI 14.1 (9.1-21.9) <.001
Day 2–7 after MI 6.0 (3.8-9.6) <.001
Day 8–30 after MI 2.1 (1.4-3.1) <.001
Day >35 after MI 1.1 (0.6-2.0) .77
Day 0–2 after major bleed* 3.5 (2.0-6.1) <.001
Day 3–7 after major bleed* 5.1 (3.3-7.8) <.001
Day 8–35 after major bleed* 2.8 (2.1-3.9) <.001
Day >35 after major bleed* 2.7 (1.9-3.9) <.001
p value HR ± 95% CI
0.5 1 2 4 8 16 32
HR (CI)
Association of MI and major
bleeding with 1-year mortality
● Time-updated Cox-proportional analysis,13819 ACUITY patients
● Risk of mortality after bleeding persists longer than after MI
Mehran R JACC. 2010;55:2556-66.
*Non-CABG major bleed.
Analysis of patients without
bleeding
● In the HORIZONS-AMI trial, treatment with bivalirudin compared to heparin +
a GP IIb/IIIa inhibitor in patients with STEMI undergoing primary PCI resulted
in significantly reduced 30-day rates of major bleeding and net adverse
clinical events
● Bivalirudin-treated patients had reduced rates of cardiac mortality, which is
usually attributed to decreased bleeding
● Whether the reduction in mortality with bivalirudin can be fully ascribed to
reduced bleeding is unknown
● Post-hoc analysis of STEMI patients with vs without major bleeding
● Time and covariate adjusted model
Stone GW TCT 2012 and JACC. 2012;60(17SupplB):B16.
HR [95%CI] =
5.81 [3.92, 8.62]
P<0.001
3.3%
11.6%
Years
Card
iac m
ort
alit
y (
%)
12% No major bleed (n=3296)
Major bleed (n=306)
10%
8%
6%
4%
2%
0%
0 1 2 3
Impact of Major Bleeding
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
14.6
3.8
5.8
2.6
0
5
10
15
Major bleeding No major bleeding
3-Y
ear
Card
iac
Mort
alit
y (
%)
Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800)
27/185 7/121 61/1617 43/1679
HR [95%CI] =
2.56 [1.12, 5.88]
P=0.02
HR [95%CI] =
1.47 [1.00, 2.17]
P=0.048
∆ = 20 deaths ∆ = 18 deaths # fewer cardiac
deaths with
bivalirudin
Pint = 0.34
3-Year Cardiac Mortality
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● In patients with vs without major bleeding, according to treatment
0
5
10
15
20
Heparin + GPIIb/IIIa (n=1721)
Bivalirudin (n=1736)
13.2%
10.1%
P=0.004
3.1%
8.1%
HR [95%CI] =
2.76 [1.85, 4.14]
P<0.001
Thrombocytopenia Years
Card
iac m
ort
alit
y (
%)
Acquired thrombocytopenia (n=404)
No thrombocytopenia (n=3053)
0
10%
8%
6%
4%
2%
0%
1 2 3
Acquired thrombocytopenia,*
in-hospital
* Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
12.3
3.5
2.3 2.5
0
5
10
15
Thrombocytopenia No thrombocytopenia
3-Y
ear
Card
iac M
ort
alit
y (
%)
Heparin + GPIIb/IIIa (n=1721) Bivalirudin (n=1736)
HR (95%CI) =
5.56 (2.00, 16.67)
P=0.0001
HR (95%CI) =
1.41 (0.47 to 1.09)
P=0.12
4/176 39/1560 28/228 52/1493
Pint = 0.006
3-year Cardiac Mortality
Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● In patients with and without thrombocytopenia, according to treatment
3-Year Cardiac Mortality
Excludes 145 patients with thrombocytopenia at baseline. Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin
Risk factor Hazard ratio (95% CI) P-value
Age (per 5 years) 1.34 (1.23 to 1.46) <0.001
WBC (per 109 cells/L) 1.15 (1.09 to 1.21) <0.001
S. creatinine (per 0.1 mg/dl) 1.10 (1.05 to 1.16) <0.001
Killip class 2-4 2.17 (1.41 to 3.35) <0.001
LAD PCI 1.68 (1.13 to 2.50) 0.007
Diabetes, medically treated 1.50 (1.01 to 2.23) 0.045
Major bleeding 2.97 (1.88 to 4.69) <0.001
Acquired thrombocytopenia 2.10 (1.36 to 3.24) 0.001
Bivalirudin (vs UFH+GPIIb/IIIa) 0.54 (0.38 to 0.79) 0.002
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
● Multivariable model, including adverse events
Conclusions
● In HORIZONS-AMI, treatment with bivalirudin rather than UFH + GPIIb/IIIa resulted in a marked reduction in cardiac mortality in patients with STEMI undergoing primary PCI
– ~ Half of the reduction in cardiac deaths with bivalirudin occurred in patients without major bleeding
● In addition to reducing major bleeding, bivalirudin reduced the occurrence of thrombocytopenia, which contributed to the improved survival in patients with and without major bleeding
● The adverse effects of major bleeding and thrombocytopenia are mitigated in patients treated with bivalirudin rather than UFH + GPIIb/IIIa, and bivalirudin was strongly associated with reduced cardiac mortality even after accounting for bleeding and thrombocytopenia – further studies are required to identify the non-hematolgic benefits of bivalirudin
Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16
ISAR REACT 4: Study Design
● Multi-centre, double-blind, double dummy drug design
* Abciximab: Bolus of 0.25 mg/kg, Infusion of 0.125 μg/kg/min for 12h UFH (=unfractionated heparin): Bolus of 70 U/kg Bivalirudin: Bolus of 0.75 mg/kg, Infusion of 1.75 mg/kg/hr for duration of PCI
Aspirin, 600mg clopidogrel
Randomised
1:1
Primary Endpoint: composite of death, large recurrent myocardial infarction, urgent target-vessel revascularisation, or major bleeding within 30 days after randomisation
Abciximab* plus UFH (n=861)
Bivalirudin* monotherapy
(n=860)
1,721 Patients with NSTEMI, Troponin +
No PCI in 2 patients No PCI in 2 patients
Kastrati A NEJM. 2011;365:1980-89.
ISAR-REACT 4: Primary endpoint
Kastrati A NEJM. 2011;365:1980-89.
0
5
10
15
20
0 5 10 15 20 25 30
Relative risk, 0.99 (95% CI, 0.74–1.32), p=0.94
Bivalirudin
UFH+Abciximab 10.9%
11.0%
Cum
ula
tive I
ncid
ence (
%)
Days since Randomization
● 30-day Death, large MI, uTVR, major bleeding
UFH=unfractionated heparin
ISAR-REACT 4: Secondary endpoints
● Major bleeding – safety secondary endpoint
Kastrati A NEJM. 2011;365:1980-89.
0
5
10
15
20
0 5 10 15 20 25 30
Days since Randomization
RR 1.82 (95% CI, 1.10–3.07), p=0.02
Bivalirudin UFH+Abciximab 4.6%
2.6%
UFH=unfractionated heparin
Cu
mu
lative
In
cid
en
ce
(%
)
Major bleeding (intracranial, intraocular, or retroperitoneal; Hb decrease >40g/L plus either overt bleeding or need for transfusion of 2 or more units)
Treatment Adjusted OR
± 95% CI Adj OR (95% Cl)
Heparin** alone
(n=1,365)
0.52 0.42, 0.65
Bivalirudin alone
(n=1,771)
0.48 0.39, 0.60
Bivalirudin + GP IIb/IIIa
(n=863)
1.23 0.98, 1.56
0 1 2
Comparisons relative to heparin** + GP IIb/IIIa (n=7086)
*Major bleeding was defined as intracranial haemorrhage, documented retroperitoneal bleed,
hematocrit (HCT) drop ≥12% (baseline to nadir ≥ 12%), any red blood cell (RBC) transfusion when
baseline HCT ≥ 28%, or any RBC transfusion when baseline HCT <28% with witnessed bleed.
**unfractionated or low molecular weight heparin
In-hospital major bleeding* by
antithrombotic strategy
Lopes RD JACC Cardiol Intv. 2010;3:669-77.
P < 0.001
In-hospital mortality by
antithrombotic strategy
Lopes RD J Am Coll Cardiol Intv. 2010;3:669-77.
Treatment Adjusted OR
± 95% CI Adj OR (95% Cl)
Heparin* alone
(n=1,365)
0.61 0.32, 1.16
Bivalirudin alone
(n=1,771)
0.39 0.21,0.71
Bivalirudin + GP IIb/IIIa
(n=863)
0.92 0.53, 1.60
0 1 2
Comparisons relative to heparin* +GP IIb/IIIa (n=7086)
P = 0.0035
*unfractionated or low molecular weight heparin
PCI – Therapeutic targets in
adjunctive pharmacotherapy
Limit
ischaemic
complications
Minimize
bleeding
Re-establish flow