Dr Jonathan Day Medical Affairs Manager
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Transcript of Dr Jonathan Day Medical Affairs Manager
Dr Jonathan Day
Medical Affairs ManagerNycomed UK Ltd., The Magdalen Centre, Oxford Science Park, Oxford, OX4 4GA
Thrombin Specific Anticoagulation
Minimising Bleeding Complications in PCI
• Speaking on behalf of Nycomed UK
Thrombin generation in PCIPlaque rupture activates coagulation generating thrombin
Forms critical link between: coagulation, inflammation and platelet activation.
Collagen
TissueFactor
ADP
TXA2
PlasmaClottingProcess
• Thrombin mediates coagulation
• Thrombin amplifies its own generation
• Thrombin is the most potent platelet agonist
Thrombin
Plateletactivation
Prothrombin
Fibrinogen Fibrin
Plateletaggregation
THROMBUS
Amplification
Coagulation
Cell membrane
Thrombin: effects beyond coagulation mediated via PARs
SR Coughlin, Nature 2000; 407: 258-264 AJ Leger et al. Circulation 2006;113;1244-1254
PAR1: A Thrombin Receptor - Sensitive to low [Thrombin]
Pro-thromboticPro-inflammatoryCell division
Thrombin antagonism with bivalirudin
• Bivalirudin is a direct and reversible thrombin-specific anticoagulant1-3
• Inhibits clot-bound and circulating thrombin
• Inhibits thrombin-mediated platelet activation / aggregation via PAR1 1-3
• Exhibits a linear and predictable dose-response profile4
– no routine ACT monitoring required3
• Bivalirudin has a short, 25-min half-life5
– coagulation times return to normal 1-2 h after treatment cessation6
1Di Nisio M et al. N Engl J Med 2005;353:1028-1040; 2Maraganore JM et al. Biochemistry 1990;29:7095-7101; 3Reed MD, Bell D. Pharmacotherapy 2002;22:105S-111S; 4Kaplan KL. Expert Opin Pharmacother 2003;4:653-666; 5Fox I et al. Thromb Haemost 1993;69:157-163; 6Veale JJ et al. J Extra Corpor Technol 2005;37:296-302.
Ischaemic protection
• Bivalirudin inhibits thrombin and thrombin-mediated platelet activation delivering ischaemic protection1,2
• Bivalirudin provides equivalent ischaemic protection to UFH/LMWH plus GP IIb/IIIa inhibitors3,4
REPLACE-2: ischaemic events (n=6002)3 ACUITY (PCI population): ischaemic events (n=7789)4
UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NS, not significant
1. Maraganore JM et al. Biochemistry 1990; 29: 7095-7101. 2. Becker R et al. J Invasive Cardiol 2003; (Suppl 1): 1-15. 3. Lincoff AM et al. JAMA 2003; 289: 853-863. 4. Stone GW et al. AHA abstract 2006.
Bleeding reduction
• The short infusion time, short half-life and reversibility of Bivalirudin reduces the risk of bleeding1,2
• Bivalirudin significantly reduces bleeding events compared with UFH/LMWH plus GP IIb/IIIa inhibitors3,4
REPLACE-2: major bleeding (n=6002)3
UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; NS, not significant
1. Reed MD, Bell D. Pharmacotherapy 2002; 22: 105S-111S. 2. Maraganore JM et al. Biochemistry 1990; 29: 7095-7101. 3. Lincoff AM et al. JAMA 2003; 289: 853-863. 4. Stone GW et al. AHA abstract 2006.
REPLACE-2: minorbleeding (n=6002)3
ACUITY (PCI population):major bleeding (n=7789)4
ACUITY (PCI population):minor bleeding (n=7789)4
Major bleeding has a considerable clinical impact
• Major bleeding associated with:
Increased in-hospital mortality 3-5
Increased long-term mortality 3-5
Increased ischaemic complications – MI and CVA 4
• Bleeding results in higher costs 6
• Transfusions independently linked to poor prognosis and mortality7
• Subgroups at higher bleeding risk include3-5,8:
Diabetes
Elderly patients
Female patients
Renal impairment
3Kinnaird TD et al. Am J Cardiol 2003;92:930-935; 4Eikelboom JW et al. Circulation 2006;114:774-782; 5Moscucci M et al. Eur Heart J 2003;24:1815-1823; 6Milkovich G, Gibson G. Am J Health Syst Pharm 2003;60(Suppl 3):S15-S21; 7Rao SV et al. JAMA 2004;292:1555-1562; 8 Stone GW. J Invasive Cardiol 2004;16(Suppl G):12-17.
Patients with diabetes have a higher incidence of bleeding in ACUITY
0
2
4
6
8
10
12
All patients Patients undergoing PCI
Patients with diabetes (n=3852 [all patients]; n=2137 [PCI])
1Feit F et al. AHA 2006 abstract; 2Feit F et al. TCT 2006 abstract 30.
Patient major bleeding events at 30 days (%)
5.7
4.2
7.5
5.3
Patients without diabetes (n=9857 [all patients]; n=5604 [PCI])
p<0.001
p<0.001
Major bleeding was significantly higher in patients with diabetes compared to those without in the total population1 and in patients undergoing PCI2
Bivalirudin protects patients with diabetes undergoing PCI in ACUITY
Angiox monotherapy provides dual ischaemic and bleeding protection in ACS patients with diabetes undergoing PCI
Feit F et al. TCT 2006 abstract 30.
0
2
4
6
8
10
12
Ischaemic composite Major bleeding
UFH / LMWH + GP IIb/IIIa inhibitors (n=703)Patient events at 30 days (%) 9.5
8.3 8.5
4.6
Bivalirudin monotherapy (n=715)p=0.NS
p<0.001
Bleeding risk increases with age in ACUITY
0
2
4
6
8
10
12
<55 55-65 65-75 >75
UFH / LMWH + GP IIb/IIIa inhibitors (n=4603)Bivalirudin monotherapy (n=4612)
Ohman EM et al. AHA 2006 abstract.
Significant increase in major bleeding with age
Patient major bleeding events at 30 days (%)
3.2
1.6
4.6
2.2
6.4
3.6
10.1
5.8
Age
p<0.0001 in both arms
Bivalirudin protects elderly ACS patients undergoing PCI
Angiox monotherapy provides ischaemic protection with significantly lower major bleeding in ACS patients >75 yrs undergoing PCI compared with heparin + GP IIb/IIIa inhibitors
Alexander KP et al. TCT 2006 abstract 37.
02468
101214161820
Ischaemic composite Major bleeding
UFH / LMWH + GP IIb/IIIa inhibitors (n=455)Patient events at 30 days (%)
11.0 12.212.3
6.1
Bivalirudin monotherapy (n=442)
p=0.NS p<0.001
And this translates into a significant difference in 1-year mortality among elderly patients (>75 years)
Lincoff AM et al. JAMA. 2004;292:696-703. Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17. Data on file, The Medicines Company.
0,0
1,0
2,0
3,0
4,0
5,0
6,0
7,0
8,0
0 60 120 180 240 300 360
Cu
mu
lative
eve
nts
(%
)
Heparin + GPIIb/IIIa (N=407)
Bivalirudin (N=388)
3.6%
6.9%
P=0.04
Time from randomization (days)1-year mortality
1 year mortality (REPLACE-2) – age >75 years
0
5
10
15
20
25
30
17.1
24.2
7.8
0.8
9.3
3.0
5.4
p<0.0001
p<0.0001
p<0.001
Major bleeding is a predictor of mortality and ischaemic complications1-3
p<0.0001
Major bleeding linked to worse patient prognosis in ACUITY
Ischaemic composite
Death MI Unplanned revascularisation
for ischaemia
5.5
Major bleeding (n=462)No major bleeding (n=7327)
1Manoukian SV et al. TCT 2006 abstract 94; 2Eikelboom JW et al. Circulation 2006;114:774-782; 3Kinnaird TD et al. Am J Cardiol 2003;92:930-935.
Patient events at 30 days (%)
Bivalirudin – a solution to a long-term problem
• Predictable control due to its unique MoA and short half-life1-5
- Protection against ischaemic events6
- Significantly reduces bleeding events in all patient
subgroups6
• Bivalirudin particularly benefits patients at high bleeding risk6
- Diabetics
- The Elderly
1Di Nisio M et al. N Engl J Med 2005;353:1028-1040; 2Maraganore JM et al. Biochemistry 1990;29:7095-7101; 3Reed MD, Bell D. Pharmacotherapy 2002;22:105S-111S; 4Fox I et al. Thromb Haemost 1993;69:157-163; 5Kaplan KL. Expert Opin Pharmacother 2003;4:653-666; 6Stone GW et al. N Engl J Med 2006.