תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי...
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תרופות נוגדות קרישה וטסיות תרופות נוגדות קרישה וטסיות בחולים העוברים צנתור כלילי בחולים העוברים צנתור כלילי
התערבותיהתערבותי
פרופ' אלי לבפרופ' אלי לב
מנהל יחידת הצנתוריםמנהל יחידת הצנתורים
ח השרון, מרכז רפואי רביןח השרון, מרכז רפואי רבין""ביבי
33 Major systems involved in Major systems involved in thrombosis and hemostasisthrombosis and hemostasis
Vessel wallVessel wall– EndotheliumEndothelium
PlateletsPlatelets
Coagulation cascadeCoagulation cascade
Anti-platelet and Anti-coagulant Properties of the Endothelium
– Covers highly thrombogenic basement membrane (collagen, TF). Uninjured endothelium does not bind platelets
– NO from uninjured endothelium inhibit platelet aggregation and adhesion, PGI2 (prostacyclin) inhibits platelet aggregation
– TFPITFPI – tissue factor pathway inhibitor – released from – tissue factor pathway inhibitor – released from endothelial cellsendothelial cells
– Endothelial cells produce t- PA which activates fibrinolysis via plasminogen to plasmin
Platelet AdhesionPlatelet Adhesion
Platelets are the first cells to adhere to Platelets are the first cells to adhere to injured vascular wall (subendothelium)injured vascular wall (subendothelium)
Adhesion is mediated by vWFAdhesion is mediated by vWF
Binding occurs only under high shear Binding occurs only under high shear stress conditions !stress conditions !
Platelet ActivationPlatelet Activation
(Plasma)
(Plasma)
(released from activated cells)
(ECM)
Platelet AggregationPlatelet Aggregation
1. Kuwahara M et al. Arterioscler Thromb Vasc Biol 2002; 22: 329–34.
FIRM, BUT REVERSIBLEADHESION
IRREVERSIBLEADHESION
Scanning electron micrograph of discoid, dormant platelets
Activated, aggregating platelets illustrating fibrin strands
Flowingdisc-shaped
platelet
Rollingball-shaped
platelet
Hemisphere-shapedplatelet
Spreadingplatelet
33 Major systems involvedMajor systems involved
Vessel wallVessel wall– EndotheliumEndothelium
PlateletsPlatelets
Coagulation cascadeCoagulation cascade
Fibrinogen FibrinThrombin
Prothrombin
XaVa
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIaIntrinsic pathway
XIIIa
Soft clot
FibrinHard clot
“Classic Coagulation Cascade”
““Classic Coagulation CascadeClassic Coagulation Cascade””
Rosenberg et al NEJM 1999
4 major Anti-thrombotic
Pathways (TFPI, Prot C/S,ATIII, Plasmin)
Localization to sitesof vascular injury.Protease complexes assemble on PLmembranes of activated platelets,endothelial cells andmonocytes. (The coagulationcascade occurs veryslowly in fluid phaseplasma and withresting cells)
From “Classic” to Current ViewFrom “Classic” to Current View
Current View of the Coagulation SystemCurrent View of the Coagulation System
InitiationInitiation by vessel wall injury which by vessel wall injury which exposes blood to cells with exposes blood to cells with TFTF on their on their surface surface TF/FVIIa activates FX TF/FVIIa activates FX Xa + Va Xa + Va cleaves II cleaves II small amounts of small amounts of IIa (thrombin) IIa (thrombin)
Minute amounts of thrombinMinute amounts of thrombin produced produced initially than lead to a marked increase in initially than lead to a marked increase in activation of FXI, FIX, FVIII, FVactivation of FXI, FIX, FVIII, FV and marked and marked generation of thrombin.generation of thrombin.
PrimingPriming invloves adherence and activation invloves adherence and activation of of plateletsplatelets.The small amounts of initial .The small amounts of initial thrombin activates platelets thrombin activates platelets release of FV release of FV + PL surface for protease activation+ PL surface for protease activation
PropagationPropagation – – an explosive increase in an explosive increase in thrombin generation thrombin generation mediated by the classic mediated by the classic “intrinsic system” “intrinsic system” FXI, FIX FXI, FIX Fxa/VIIIa/Va Fxa/VIIIa/Va on activated platelets on activated platelets IIa + fibrin formation IIa + fibrin formation
Schneider D et al, Circulation 2007
““The Great BalanceThe Great Balance””
Thrombotic Complications
Bleeding Complications
Mo
rtal
ity
(%)
Days from Randomization
0 30 60 90 120 150 180 210 240 270 300 330 360 3900
5
15
30
10
25
20
1 yearEstimate
Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)
3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%
Significance of bleeding: Impact of MI and Major Bleeding (non-CABG) in first 30 Days on Risk of Death Over 1 Year
28.9%
12.5%
8.6%
3.4%
ACUITY – 1 year
Courtesy of Dr S. Steinhubl, U. Kentucky
100
200
300
400
500
600
0 7 14 21 28 35
Placebo alone:568/4300 (13.2%)
Aspirin alone:461/4295 (10.7%)
Streptokinase alone:448/4300 (10.4%)
Streptokinase plus aspirin:343/4292 (8.0%)
Cu
mu
lati
ve N
um
ber
of
Vas
cula
r D
eath
s
Days From Randomization
Aspirin in Acute Myocardial Infarction: Aspirin in Acute Myocardial Infarction:
ISIS-2ISIS-2 (Lancet (Lancet 1988;2:349-60)1988;2:349-60)
Aspirin in the Treatment of ACSAspirin in the Treatment of ACS
Wallentin LC, et al. JACC 1991;18:1587-93.
0.00
0.05
0.10
0.15
0.20
0.25
0 3 6 9 12Months
Pro
bab
ilit
yo
f D
eath
or
MI
Placebo
Aspirin 75 mg
Risk ratio 0.5295% CL 0.37-0.72
Comparison of ASA Doses on Vascular Comparison of ASA Doses on Vascular Events in High-Risk PatientsEvents in High-Risk Patients
* Odds reduction. Treatment effect P<.0001.ASA, acetylsalicylic acid.Adapted with permission from BMJ Publishing Group. Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.
0.5 1.0 1.5 2.0
500-1500 mg 34 19
160-325 mg 19 26
75-150 mg 12 32
<75 mg 3 13
Any aspirin 65 23
Antiplatelet Better Antiplatelet Worse
Aspirin Dose No. of Trials (%) Odds Ratio
0
OR*
ClopidogrelClopidogrel
Efficacy of anti-platelet agents in reducing coronary events after stenting
Cumulative event rate(%)
CURE TRIAL – ACS pts
20 % reduction in primary endpoint (N Engl J Med. 2001;345:494-502)
PCI-CURE TRIAL – ACS pts
Pretreatment with clopidogrel vs. no pretreatmentReduction in CV death, MI or urgent TVR
CURE Investigatots, Lancet 2001 358: 527-33
Distribution of Response to Distribution of Response to ClopidogrelClopidogrel (544 patients, platelet aggregation)(544 patients, platelet aggregation)
Change in Aggregation to 5µM ADP
Number of patients
0
16
32
48
64
80
96
112
- =<20 -[10,0] [11,20] [31,40] [51,60] [71,80] [91,100]
Serebrauny V et al. JACC 2004
PLATELET FUNCTION ASSAYS REVEALE EXTREME INTER-PATIENT VARIABILITY*
Courtesy of Aradi, Collet .
*After 600 mg clopidogrel loading dose, in patients with stable angina undergoing PCI
ADAPT-DES: DEFINITE / PROBABLE ST @ 30 days
Stone et al, Lancet 2013
Low response to clopidogrel in Low response to clopidogrel in patients with ACS: patients with ACS: RECLOSE-2RECLOSE-2
P=0.003
P<0.001
1789 patients with ACS
High on treatmentplatelet reactivity (low
response) determined byLTA in response to ADP
14% of pts had HTPR
Primary endpoint = cardiac death, MI ,
urgent revasc. or stroke
Antoniucci et al, JAMA 2011
Prasugrel: Active Metabolite FormationFaster Onset of IPA
Prasugrel: Active Metabolite FormationFaster Onset of IPA
HOOCHOOC
* HS* HS
NN
OO
FF
NN
SS
OO
CCHH33
CCOO
FF
PrasugrelPrasugrelPrasugrelPrasugrel
Pro-drugPro-drugPro-drugPro-drug
Hepatic MetabolismHepatic MetabolismCytochrome P450Cytochrome P450
Hepatic MetabolismHepatic MetabolismCytochrome P450Cytochrome P450
Active MetaboliteActive MetaboliteActive MetaboliteActive Metabolite
NN
SS
OO
FFOO
HOOCHOOC
* HS* HS
NN
OO
ClCl
OCH3OCH3
Sem Vasc Med 3:113, 2003Sem Vasc Med 3:113, 2003
Pre-hepatic Pre-hepatic metabolism - metabolism - HydrolysisHydrolysis
Esterases in blood Esterases in blood
Pre-hepatic Pre-hepatic metabolism - metabolism - HydrolysisHydrolysis
Esterases in blood Esterases in blood
OO
85% 85% Inactive Inactive
MetabolitesMetabolites(hydrolysis)(hydrolysis)
85% 85% Inactive Inactive
MetabolitesMetabolites(hydrolysis)(hydrolysis)
OONN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
NN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
NN
SS
OO
ClCl
OO CHCH33CHCH33CCCC
ClopidogrelClopidogrelClopidogrelClopidogrel
* * * * * * **
Prasugrel 10 mg MD vs. Clopidogrel 75 mg Prasugrel 10 mg MD vs. Clopidogrel 75 mg MD: Higher IPA During Maintenance DosingMD: Higher IPA During Maintenance Dosing
mean ± SEMmean ± SEM 20 20 μμM ADPM ADP
Inh
ibit
ion
of
Pla
tele
t A
gg
reg
atio
nIn
hib
itio
n o
f P
late
let
Ag
gre
gat
ion
(%)
(%) 00
2020
4040
6060
8080
100100Loading DoseLoading Dose
Maintenance DosesMaintenance Doses
TimeTimeHoursHours DaysDays
0.250.25 0.50.5 11 22 44 66 2424 33 44 55 66 77 88 9900
Clop 300 mg
Clop 75 mg
††
!
!
† §
* PP<0.001 vs. Clop 300 mg<0.001 vs. Clop 300 mg or 600 mg LD or 600 mg LD
† PP<0.001 vs. Clop 300<0.001 vs. Clop 300
! PP<0.05 vs. Clop 300<0.05 vs. Clop 300§ PP<0.05 vs Clop 300/75<0.05 vs Clop 300/75
Clop 600 mg
Clop 75 mg
*
*
* * *
Pras 60 mg
Pras 10 mg
Payne CD et al. Presented at TCT 2006.
CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; MI=Myocardial Infarction; TIMI=Thrombolysis In Myocardial Infarction
Prasugrel
Clopidogrel
TRITON-TIMI 38: Rates of Key Study End Points (13,500 pts with ACS)
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
5
10
15
00 30 60 90 180 270 360 450
Days After Randomization
En
d P
oin
t (%
)
120
1.8 (111)
2.4(146)
Non-CABG TIMI Major Bleeds
CV Death, MI, Stroke
P=0.03
P<0.001↓138 events
↑ 35 events
12.1(781)
9.9 (643)
Prasugrel
Clopidogrel
TRITON-TIMI 38: ARC Definite/Probable Stent Thrombosis:
ARC=Academic Research Consortium; ARR=Absolute Risk Reduction; HR=Hazard Ratio; NNT=Number Needed to Treat; PCI=Percutaneous Coronary Intervention; RRR=Relative Risk Reduction Wiviott SD et al. Lancet 2008;371:1353-1363
0 30 60 90 180 270 360 450
HR 0.48 (0.36-0.64)P<0.0001
RRR 52%ARR 1.22%
Prasugrel
Clopidogrel2.35
1.13
Days
Ste
nt
Th
rom
bo
sis
(%)
Any Stent at Index PCI n=12,844
0
1
2
3
NNT=77NNT=77
ACS=Acute Coronary Syndrome; CABG=Coronary Artery Bypass Graft surgery; HR=Hazard Ratio; TIMI=Thrombolysis In Myocardial Infarction
P=0.002
Odds Ratio 4.73P<0.001
TIMI Major or Minor
CABG-related TIMI Major Bleeding
Requiring Transfusion
P<0.001
At risk 6/189
At risk 24/179
)n=6,716(
)n=6,741(
En
d P
oin
t(%
)
3.2%
13.4%
n=244n=182
n=231
n=3033.8%5.0%
3.0%4.0%
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
TRITON-TIMI 38: TIMI Bleeds at 15 mo TRITON-TIMI 38: TIMI Bleeds at 15 mo (all ACS)(all ACS)
TIMI major bleeding :1.8% vs. 2.4%,
(P=0.03), Pras vs. Clop
Bleeding Risk SubgroupsBleeding Risk SubgroupsTherapeutic ConsiderationsTherapeutic Considerations
Significant Net Clinical Benefit
with Prasugrel80%
Reduced MD
Guided by PK
Age < 75 or
Wt < 60 kg
16%
Avo
id
Prasu
grel
Prio
r
CV
A/T
IA4%4%
TRITON-TIMI 38, NEJM 2007
TRITON-TIMI 38: TRITON-TIMI 38: Diabetic SubgroupDiabetic Subgroup Analysis (n=3,146)Analysis (n=3,146)
CABG=Coronary Artery Bypass Graft surgery; CV=Cardiovascular; HR=Hazard Ratio; MI=Myocardial Infarction; NNT= Number Needed to Treat; TIMI=Thrombolysis In Myocardial Infarction
Adapted from Antman EM et al. American Heart Association Scientific Sessions; 2007, Nov 4-7; Orlando, FL
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
d P
oin
t(%
)
CV Death, MI, Stroke
NNT=21
17.0
12.2
2.62.5
Non-CABG TIMI Major Bleeds
Prasugrel
Clopidogrel
TRITON-TIMI 38: TRITON-TIMI 38: STEMI SubgroupSTEMI Subgroup Analysis (n=3,534)Analysis (n=3,534)
0
1
2
3
4
5
6
7
All causeDeath
CV death RE-MI Stentthrombosis
Non CABGbleeding
Prasugrel
Clopidogrel
P=0.05P=0.05P=0.045P=0.045
P=0.01P=0.01
P=0.01P=0.01 P=0.4P=0.4
Ticagrelor (AZD 6140): an oral reversibleP2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
• Direct acting – Not a prodrug; does not require metabolic activation
– Rapid onset of inhibitory effect on the P2Y12 receptor
– Greater and more consistent inhibition of platelet aggregation versus clopidogrel
• Reversibly bound– Degree of inhibition reflects plasma concentration– Faster offset of effect than clopidogrel – Functional recovery of all circulating platelets
OH
OH
O
OH
N
S
NH
NN
NN
F
F
LastMaintenance
Dose
Loading Dose
Time (hours) Onset Maintenance Offset
100
90
80
70
60
50
40
30
20
10
0
IP
A%
Ticagrelor (n=54)
Clopidogrel (n=50)Placebo (n=12)
0. 5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240
*
*
* **
*
*
*
*
‡
†
†
Onset / Offset Study, IPA to 5uM ADP
Gurbel PA et al. Circulation 2009Gurbel PA et al. Circulation 2009
PLATO study primary efficacy event - CV death, MI or stroke (18,600 pts with ACS)
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
121110
9876543210
13
Cu
mu
lati
ve in
cid
ence
(%
)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
K-M estimates of time to secondary efficacy endpoints
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cu
mu
lati
ve i
nci
de
nce
(%
)
Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Myocardial infarction Cardiovascular death !!!
Cu
mu
lati
ve i
nci
de
nce
(%
)
Stent thrombosisStent thrombosis
Evaluated in patients with any stent during the study
0
0.5
1
1.5
2
2.5
3
Definite Definite orProbable
Ticagrelor
Clopidogrel
Wallentin et al, N Engl J Med 2009Wallentin et al, N Engl J Med 2009
P=0.01P=0.01 P=0.02P=0.02
%%
Major bleeding – primary safety event
No. at risk
Clopidogrel
Ticagrelor
9,186
9,235
7,305
7,246
6,930
6,826
6,670
Days from first IP dose
5,209
5,129
3,841
3,783
3,479
3,433
0 60 120 180 240 300 360
10
5
0
15
Clopidogrel
Ticagrelor
11.2011.58
6,545
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-M
est
imat
ed r
ate
(% p
er y
ear)
Non-CABG and CABG-related major Non-CABG and CABG-related major bleedingbleeding
p=0.026
p=0.025
NS
NS
9K
-M e
stim
ated
rat
e (
% p
er y
ear)
Non-CABGPLATO major
bleeding
8
7
6
5
4
3
2
1
0Non-CABGTIMI major bleeding
CABGPLATO major
bleeding
CABG TIMI major bleeding
4.5
3.8
2.8
2.2
7.4
7.9
5.3
5.8
TicagrelorClopidogrel
Dyspnoea with TicagrelorDyspnoea with Ticagrelor
All patientsAll patients
TicagrelorTicagrelor
(n=9,235) (n=9,235)
ClopidogrelClopidogrel
(n=9,186)(n=9,186)p valuep value**
Dyspnoea, %Dyspnoea, %
Any Any
Requiring discontinuation of study Rx Requiring discontinuation of study Rx
13.813.8
0.90.9
7.87.8
0.10.1
<0.001<0.001
<0.001<0.001
“Ticagrelor-related dyspnoea is usually mild or moderate in intensity, self-limiting and does not appear to be associated with differences in any efficacy or safety outcomes with ticagrelor compared with clopidogrel therapy in ACS pts”.
Storey et al, Eur Heart J 2011
PLATO STEMI - Primary endpoint: PLATO STEMI - Primary endpoint: CV death, MI or strokeCV death, MI or stroke
0123456789101112
12
11
10
9
8
7
6
5
4
3
2
1
0
Months
HR: 0.85 (95% CI = 0.74–0.97), p=0.02
No. at risk
Clopidogrel
Ticagrelor
4,229
4,201
3,892
3,887
3,823
3,834
3,730 3,022
3,011
2,333
2,297
1,868
1,8913,732
11.0
9.3
Clopidogrel
Ticagrelor
K-M
est
ima
ted
rat
e (%
per
ye
ar)
Steg et al, Circulation 2010
PLATO STEMI - All cause mortalityPLATO STEMI - All cause mortality
0123456789101112
7
6
5
4
3
2
1
0
K-M
est
imat
ed r
ate
(% p
er y
ear)
4,2014,0053,9623,8763,1502,4131,9934,2294,0293,9893,9123,1952,4711,980
MonthsNo. at riskTicagrelor
Clopidogrel
Clopidogrel
Ticagrelor
4.9
6.0
HR 0.82 (95% CI = 0.68–0.99), p=0.04
K-M
est
imat
ed r
ate
(% p
er y
ear)
0123456789101112
10
8
6
4
2
0
Months No. at riskTicagrelor
Clopidogrel4,1653,4313,2543,1372,4401,7861,6404,1813,4303,2973,1592,4411,8041,635
Clopidogrel
Ticagrelor 9.0
9.3
PLATO STEMI - Primary safety PLATO STEMI - Primary safety event: major bleedingevent: major bleeding
HR 0.96 (95% CI = 0.83–1.12), p=0.63
Steg et al, Circulation 2010
Platelet ActivationPlatelet Activation
)Plasma(
)Plasma(
)released from activated cells(
)ECM(
GP IIb/IIIA Inhibitors
Abciximab (ReoPro) – the first inhibitor developed and approved for clinical use.Chimeric monoclonal antibody – 7E3, the murine constant region was replaced by its human counterpart
Eptifibatide (Integrilin) – synthetic cyclic hepta-peptide derived from a sequence found in the venom of the southeastern pygmy rattlesnake
Tirofiban (Aggrastat) – synthetic small molecule with structure similar to that of the RGD sequence of the snake venom echistatin
Glycoprotein IIb/IIIa Receptor AntagonistsGlycoprotein IIb/IIIa Receptor Antagonists
0.25 mcg/kg bolus followed by 0.125 mcg/kg/min drip (max 10 mcg/min) for 12-24 hours
Synthetic non-peptide
0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min drip for 48-96 hours
Cyclic heptapeptide
180 mcg/kg bolus (x2) followed by 2.0 mcg/kg/min drip for 18-24 hours
Fab portion of chimeric monoclonal antibody
30 minutes 1.8 hours 2.5 hours
Not specific Highly specific Highly specific
Abciximab Tirofiban Eptifibatide
Pharma
Plasma ½ life
Specificity
Dose
1.6%
10.5%
11.5%
1.2%1.1%
8.1%8.6%
1.0%
0%
5%
10%
Death MI Death/MI Urg Revac
Placebo
Abciximab
ISAR-REACT 2ISAR-REACT 2High-risk ACS Patients – 30 Days High-risk ACS Patients – 30 Days
p=0.06p=0.03
p=0.34 p=0.64
JAMA 2006;295:1531-38JAMA 2006;295:1531-38
Abciximab in Primary PCI Meta-analysisAbciximab in Primary PCI Meta-analysis8 RCTs – 3,949 pts with AMI w/i 128 RCTs – 3,949 pts with AMI w/i 12 undergoing primary (7) or undergoing primary (7) or
rescue (1) PCI rand to abciximab vs. placebo or controlrescue (1) PCI rand to abciximab vs. placebo or control
p=0.06p=0.06RR 0.71 RR 0.71
]0.49,1.02[]0.49,1.02[
p=0.01p=0.01RR 0.72 RR 0.72
]0.55,0.94[]0.55,0.94[
66––1212 monthsmonths
De Luca G et al. De Luca G et al. JAMAJAMA 2005;293:1759–1765 2005;293:1759–1765
Updated meta-analysis of effect of Updated meta-analysis of effect of GPIs on GPIs on 30 day mortality30 day mortality in pts with in pts with
STEMISTEMI
De Luca rt al, EHJ 2009
Favors GPIs Favors Control
Updated meta-analysis of effect of GP Updated meta-analysis of effect of GP IIb/IIIa inhibitors on IIb/IIIa inhibitors on 30 day re-MI30 day re-MI
De Luca rt al, EHJ 2009
Favors GPIsFavors control
Updated meta-analysis of effect of GP Updated meta-analysis of effect of GP IIb/IIIa inhibitors on IIb/IIIa inhibitors on major bleedingmajor bleeding
De Luca rt al, EHJ 2009
C-terminal dodecapeptide(Exosite 1-binding portion)
(Gly)4
D-Phe-Pro-Arg-Pro(active-site-binding moiety)
C-terminal dodecapeptide(Exosite 1-binding portion)
(Gly)4
D-Phe-Pro-Arg-Pro(active-site-binding portion)
2
1
Thrombin
BivalirudinBivalirudinBivalirudin – a direct thrombin inhibitor - binds bivalently and with high affinity to thrombin’s active siteBivalirudin – a direct thrombin inhibitor - binds bivalently and with high affinity to thrombin’s active site
A/BR//259.a.1
2
1
Thrombin
Bivalirudin can displace fibrin bound to Bivalirudin can displace fibrin bound to thrombinthrombin——
Bivalirudin has high specificity for thrombinBivalirudin has high specificity for thrombin..
BivalirudinBivalirudin
A/BR//260.a.1
BivalirudinBivalirudin
Bivalirudin is cleared from plasma by combination of Bivalirudin is cleared from plasma by combination of renal mecahnisms and proteolytic cleavagerenal mecahnisms and proteolytic cleavage
Plasma half life = 25 minutes (norm renal funct)Plasma half life = 25 minutes (norm renal funct)
Mod. renal impairment, half life = 34 minutes (dose Mod. renal impairment, half life = 34 minutes (dose reduced) reduced)
Almost immediate prolongation of ACT. aPTTAlmost immediate prolongation of ACT. aPTT
Coagulation times return to normal after about 1 hour Coagulation times return to normal after about 1 hour following drug d/cfollowing drug d/c
No HIT !!No HIT !!
HORIZONS 1-Year Major Adverse CV Events3602 patients with STEMI undergoing 1o PCI
Number at riskNumber at riskBivalirudin aloneBivalirudin aloneHeparin+GPIIb/IIIaHeparin+GPIIb/IIIa
Bivalirudin alone (n=1800))
Heparin + GPIIb/IIIa (n=1802)
1800 1627 1579 1544 13941802 1619 1573 1540 1380
MA
CE
(%
)
0123456789
101112131415
Time in Months
0 1 2 3 4 5 6 7 8 9 10 11 12
11.9%11.9%11.9%11.9%
Diff ]95%CI[ = 0.0% ]-2.1, 2.2[
HR ]95%CI[ = 1.00 ]0.83, 1.21[
P=0.98
**MACE = All cause death, reinfarction, ischemic TVR or stroke
Number at riskNumber at riskBivalirudin aloneBivalirudin aloneHeparin+GPIIb/IIIaHeparin+GPIIb/IIIa
1800 1621 1601 1586 14481802 1544 1532 1515 1368
Ma
jor
Ble
ed
ing
(%
)
0
1
2
3
4
5
6
7
8
9
10
11
12
Time in Months
00 11 2 3 4 5 6 7 8 9 10 11 12
9.2%9.2%
5.8%5.8%Diff ]95%CI[ = -3.4% ]-Diff ]95%CI[ = -3.4% ]-
5.2, -1.7[5.2, -1.7[22
HR ]95%CI[ =HR ]95%CI[ =
0.61 ]0.48, 0.78[ 0.61 ]0.48, 0.78[
P<0.0001P<0.0001
1-Year Major Bleeding (non-CABG)
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
1-Year Mortality: Cardiac and Non Cardiac
Number at riskNumber at riskBivalirudin aloneHeparin+GPIIb/IIIa
Bivalirudin alone (n=1800)
Heparin + GPIIb/IIIa (n=1802)
1800 1705 1684 1669 15201802 1678 1663 1646 1486
CardiacCardiac
Non CardiacNon Cardiac
Mo
rtal
ity
(%)
0
1
2
3
4
5
Time in Months
0 1 2 3 4 5 6 7 8 9 10 11 12
3.8%
2.1%
1.3%1.1%
HR ]95%CI[ =0.57 ]0.38, 0.84[
P=0.005
2.9%
1.8%
Δ = 1.1%P=0.03
Δ = 1.7%
NCDR PCI registry including >1,500,000 pts NCDR PCI registry including >1,500,000 pts undergoing PCI in 955 US hospitalsundergoing PCI in 955 US hospitals
23% of the patients treated with bivalirudin23% of the patients treated with bivalirudin
50% elective, 36% urgent, 14% emergent PCI50% elective, 36% urgent, 14% emergent PCI
Bivalirudin associated with OR 0.67 (0.63-0.70) Bivalirudin associated with OR 0.67 (0.63-0.70) for bleeding events !! for bleeding events !! (Bleeding defined as requiring (Bleeding defined as requiring blood transfusion, prolonged hospital stay, or blood transfusion, prolonged hospital stay, or ↓ ↓ 3 g/dL in Hg)3 g/dL in Hg)
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