angiomax (bivalirudin) in peripheral vascular disease (pvd)
TRANSCRIPT
Angiomax (bivalirudin) in Peripheral Vascular Disease (PVD)
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Anticoagulation in PVD
► Thrombus occurs in 100% of peripheral percutaneous intervention (PPI) cases
► Bleeding risks are greater in PPI than PCI
► PPI and PCI are different
► PPI requires superior anticoagulation
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Clinical Differences in PVD vs. PCI
► Longer length diseased vessel
► Larger sheath size requirement
► Longer PTA/stented segments
► Larger acute and chronic thrombus burden
► Longer procedural times (sheath dwell times)
► Multiple catheter, guidewire, devices, etc exchanges (oftentimes crossover techniques)
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Clinical Differences in PVD vs. PCI (con’t)
► “Low flow” state in peripheral versus coronary flow beds
► Increased incidence of CRF (renal insufficiency)
► Postprocedural anticoagulation (infrainguinal, limb salvage, ALI, etc.)
► PVD- > 50-60% Diabetes: PCI- 20-30% Diabetes
► PVD patients are hypercoaguable
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Peripheral interventions
► Percutaneous peripheral interventions (PPI) require predictable and reliable anticoagulation that also minimizes risk of bleeding
Large sheaths
Renal dysfunction
Long interventions
► Strategies needed to improve throughput
Reduce time to sheath removal
Reduce time to ambulation
► Heparin is typically used in PPI, but no data exist on the optimal level of anticoagulation
► The limitations of heparin persist in PPI…
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Bivalirudin in peripheral interventions
► Bivalirudin: a thrombin-specific anticoagulant, superior efficacy, significantly less bleeding vs heparin in PTCA1
► Bivalirudin used in PPI registries: St Joseph’s, Naples Endovascular, Cardiovascular Institute of the South, Cardiovascular Research Foundation/Lenox Hill
► Based on these limited data, bivalirudin may be an attractive alternative to heparin in peripheral interventions
► May offer decreased vascular complications, earlier sheath removal time, earlier ambulation and decreased length of stay
► Further studies are warranted
1Bittl et al AJC 2001
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Overview
Peripheral experienceSt Joseph’s Hospital Registry
Naples Endovascular
Cardiovascular Research Foundation & Lenox Hill
Cardiovascular Inst of the South
Angiomax clinical program APPROVE trial
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St. Joseph’s Hospital Registry
► 72 Patients, elective procedures
► 88 Lesions (4 with concomitant PCI)
► Mean Age 65.8 yrs (Range 43-84)
► 60% Male
► 73% HTN
► 23% Diabetes
► Prior MI 25%
► Prior PCI 62%
► Prior CABG 27%
► Prior CVA 10%
Knopf et al, TCT 2002
Demographics
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St. Joseph’s Hospital Registry
► Bivalirudin bolus 0.75mg/kg in 100%
► Infusion 1.75 mg/kg/hr used in 50% of cases
► Mean ACT 286.6 (224-389)
► Sheath 6F-11F
► Mean creatinine pre 1.17 (0.7-2.7)
► Plavix 99%
► GP IIb/IIIa 0%
► Closure devices 20%
Knopf et al, TCT 2002
Methods
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Location of the 88 lesions
► Iliac 33
► Renal 26
► Femoral 12
► Carotid 16
► Distal Aorta 1
► Subclavian 1
Knopf et al, TCT 2002
St. Joseph’s Hospital Registry
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Results► Success 100%
► Bleeding 0%
► Mortality 0%
► Subacute closure 0%
► Vascular repair 0%
► CVA 0%
► Post-procedure creatinine increase > 0.5 0%
► Mean sheath removal 108 minutes
► LOS 0.6 days (0-2)
Knopf et al, TCT 2002
St. Joseph’s Hospital Registry
Naples Endovascular Registry
Grubbs, CRT 2003
Type N cases Bivalirudin Rx Success rate
Arterial lysis 12 bolus+ inf 100%
Endovascular AAA 8 bolus+ inf 100%
Carotid art. stent 3 bolus+ inf 100%
Venous interventions 13 bolus 94%
Arterial interventions 16 bolus 100%
Venous dialysis
Graft declots w/lytic
13 bolus 100%
Venous dialysis
Graft declots w/mech device
4 bolus 100%
69 proceduresBivalirudin bolus 0.75mg/kg Infusion 1.75 mg/kg/hr
Naples Endovascular Registry
Grubbs, CRT 2003
• Bivalirudin provided adequate anticoagulation for all peripheral interventions
• Achieved ACT targets immediately
• No adverse events (bleeding, procedural failure, acute thrombosis, or death) were seen.
• Historical analysis of usual complication rates for this composite set of procedures w/ heparin= 6% >1200 interventions.
• Bivalirudin procedural success rate of 100% on 12 consecutive arterial lysis cases is of note, historical complete lysis rate of 78% in >100 cases using tPA alone during the past 4 years.
Conclusions
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Cardiovascular Research Fdn& LHH
► 59 consecutive pts with bivalirudin (bolus 75mg/kg, 1.75 mg/kg/hr infusion throughout the procedure)
► 83 case-matched controls with UFH (5,000U), same timeframe
► mean age = 72 + 9 yrs
► 60.4% male
► No GP IIb/IIIa inhibitors
► Neurological events, bleeding and vascular complications were recorded and adjudicated by an independent committee
Adamyan et al, ACC 2003
Carotid Stenting
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Cardiovascular Research Fdn& LHH
Adamyan et al, ACC 2003
Clinical Outcomes Bivalirudin n=59
UFH n=83
P value
Death , n% 0 (/59) 0 (0/83) NS
Major stroke, n% 0 (0/59) 1.2 (1/83) 1.00
Minor stroke, n% 0 (0/59) 0 (0/83) NS
Hematoma > 5cm (%) 1.7 (1/59) 3.6(3/83) 0.64
Pseudoaneurysm(%) 0 (0/59) 2.4 (2/83) 0.51
Transfusion (%) 0 (0/59) 8.6 (7/81) 0.02
Vascular complication 1.7 (1/59) 4.9 (4/81) 0.39
Results
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Bivalirudin in peripheral interventions
► Based on these limited data, bivalirudin may be an attractive alternative to heparin in peripheral interventions
► May offer decreased vascular complications, earlier sheath removal time, earlier ambulation and decreased length of stay
► Further studies are warranted
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Direct Thrombin Inhibition in PVD
Bivalirudin as Sole Anticoagulant in Peripheral Vascular Disease: A Safety and Feasible Alternative in Renal and Iliac Interventions
David E. Allie, Mitchell D. Lirtzman, V. Antoine Keller, Mohamed H. Khan, Muhammad A. Khan, Peter S. Fail, Chris J. Hebert, Adam A. Allie, Craig M. Walker, Cardiovascular Institute of the South, LA, HCA, LA
Allie et al ACC 2003
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Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA
Design/ Methods
• Retrospective, consecutive review of 180 renal, 75 iliac
• Bivalirudin: 0.75 mg/kg bolus with 1.75 mg/kg/hr infusion for procedural duration
• Variables: Sheath removal time (SRT), access complication (AC), time to ambulate (TA), and length of stay (LOS).
• Follow up: 6 month renal and iliac duplex ultrasound and ankle-brachial index
• Matched historical control with UFH
Allie, ACC 2003
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Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA
Results:
Allie, ACC 2003
Variables Bivalirudin Renal, n=180
Historical Control Renal, n=180
P-value
PPI Success, n (%) 180 (100) 179 (99) 0.31 73 AC (Major1), n (%) 2(1.1) 6 (3.3) 0.1532 AC (Minor2), n(%) 5(2.7) 8 (4.4) 0.3974 SRT <60 min, n (%) 152 (84) 106 (59) <0.0001 SRT >60 m in, n (%) 28 (16) 74 (41) <0.0001 LOS <24 hrs, n (%) 154(85.5) 130 (72) 0.002 LOS >24 hrs, n (%) 26(14.5) 50 (28) 0.002 TA <6 hrs, n (%) 136(75.5) 105 (58) 0.0005 TA >6 hrs, n (%) 44(24.5) 75 (42) 0.0005
1="Major’ = any surgery, > 5 cm hematoma, or > 2u transfusion2="Minor’ = all other non-intracranial or retroperitoneal bleeding
RT, LOS and TA all significantly shorter with bivalirudin
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Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA
Results
Allie, ACC 20031="Major’ = any surgery, > 5 cm hematoma, or > 2u transfusion2="Minor’ = all other non-intracranial or retroperitoneal bleeding
Variables Bivalirudin Iliac n=75
Historical control Iliac n=75
P-value
PPI Success, n (%) 75 (100) 74 (98.6) 0.3173
AC (Major1), n (%) 2(2.5) 3 (4) 0.6503
AC (Minor2), n(%) 3(4) 5 (6.6) 0.4689
SRT <60 min, n (%) 36 (48) 21 (28) 0.0119
SRT >60 min, n (%) 39 (52) 54 (72) 0.0119
LOS <24 hrs, n (%) 42(56) 32 (43) 0.1036
LOS >24 hrs, n (%) 33(44) 43 (57) 0.1036
TA <6 hrs, n (%) 31(41) 19 (25) 0.0383
TA >6 hrs, n (%) 44(59) 56 (75) 0.0383
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► Procedural success and clinical outcomes similar in both PVD groups with bivalirudin and UFH
► Fewer access site complications in all groups
Renal Iliac
Bivalirudin UFH BivalirudinUFH
Overall 3.9% 7.7% 6.5%10.6%
Major 1.1% 3.3% 2.5% 4.0%
Minor 2.7% 4.4% 4.0%6.6%
Overall Access Site ComplicationsBivalirudin = 3.8% UFH = 6.6%
Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA
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Bivalirudin as Anticoagulant Foundation in PVD: A Safety and Feasibility Study in Renal and Iliac PTA
► No thrombotic events, intracranial bleeding, or major surgical complications occurred in bivalirudin group
► Sheath removal time, time to ambulation and length of stay were reduced compared to historical control
► 6 month repeat PPI:
Renal 7/180 (3.9%) bivalirudin 8/180 (5%) UFH
Iliac and 3/75 (4%) bivalirudin 4/75 (5.3%) UFH
Allie, ACC 2003
Principal Investigators:
David Allie MD Cardiovascular Institute of the South Patrick Hall MD South Carolina Heart Center
Direct Thrombin Inhibition in PVD
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To demonstrate that Angiomax can safely replace unfractionated heparin as the primary anticoagulant in patients undergoing peripheral interventions, including outpatient interventions (<23hour)
Open label trial of Angiomax anticoagulation in renal, femoral, and Iliac lesions
505 patients
26 sites
Study Objective and Design
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Angiomax 0.75 mg/kg IV bolus + 1.75 mg/kg-hr IV
infusion for duration of procedure
GP IIb/IIIa’s at physician discretion
Bivalirudin post-procedural infusion 0.25 mg/kg/hr at physician discretion
Study Drug Administration
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Primary: Procedural success defined as ≤ 20% residual stenosis as determined by the treating physician.
Secondary:
· Activated clotting times (ACTs)
· Health economics (sheath size, time to sheath removal, time to ambulation, time to discharge, use of closure devices)
· Death
· Bleeding
· Myocardial infarction (MI)
· Unplanned revasc or surgical intervention for ischemia
· Amputation
· Renal function (relation to ischemic and bleeding outcomes).
Endpoints
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Primary lesion/vessel
• Renal n/N (%) 173/505 (34.3)
• Iliac n/N (%) 140/505 (27.7)
• Femoral n/N (%) 184/505 (36.4)
• Other n/N (%) 8/505 (1.6)
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► Clopidogrel pretreatment 95%
► Aspirin 96.8%
► GP IIb/IIIa inhibitors 4.4%
► Procedural success 95%
Procedural characteristics
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Patient demographics
Characteristic
Age (mean) 69
Age > 65 yrs n/N (%) 320/505 (63.4)
Age > 75 yrs n/N (%) 164/505 (32.5)
Female n (%) 231 (45.7)
Male n (%) 274 (54.3)
Angina History n/N (%) 178/504 (35.3)
Prior MI n/N (%) 124/505 (24.6)
Prior Vascular Surgery n/N (%) 175/505 (34.7)
Current Smoker (<6 mos) n/N (%) 152/505 (30.1)
Hyperlipidemia n/N (%) 400/505 (72.9)
Hypertension n/N (%) 450/504 (89.3)
Congestive Heart Failure n/N (%) 79/505 (15.6)
Diabetes (insulin-dependent) n/N (%) 63/505 (12.5)
Diabetes (non insulin-dependent n/N (%) 120/505 (23.8)
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Ischemic outcomes: 30 days
Renal Iliac Femoral Total
n/N (%) n/N (%) n/N (%) n/N (%)
Death 0/173 (0.0) 0/139 (0.0) 0/184 (0.0) 0/505 (0.0)
Unplanned revasc 0/173 (0.0) 0/139 (0.0) 4/184 (2.2) 4/504 (0.8)
Amputation 0/173 (0.0) 0/139 (0.0) 2/184 (1.1) 2/504 (0.4)
Myocardial infarction
0/173 (0.0) 0/139 (0.0) 1/184 (0.5) 1/505 (0.2)
New Q- wave* 0/173 (0.0) 0/139 (0.0) 0/184 (0.0) 0/505 (0.0)
CK-MB>3XULN 0/173 (0.0) 0/139 (0.0) 1/184 (0.5) 1/505 (0.2)
* New Q-wave >0.04 sec duration in 2 or more contiguous leads
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Hemorrhagic outcomes: 30 days
Renal Iliac Femoral Total
n/N (%) n/N (%) n/N (%) n/N (%)
Major (protocol) 7/173 (4.0) 5/140 (3.6) 7/184 (3.8) 19/505 (3.8)
Tfx ≥2 U 3/173 (1.7) 5/140 (3.6) 3/184 (1.6) 11/505 (2.2)
Intracranial 0/173 (0.0) 0/139 (0.0) 1/184 (0.5) 1/504 (0.2)
Retroperitoneal 0/173 (0.0) 1/139 (0.7) 1/184 (0.5) 2/504 (0.4)
Fall in Hgb >4g/dL w/no site
2/173 (1.2) 3/140 (2.1) 4/183 (2.2) 9/505 (1.8)
Fall in Hgb >3g/dL overt
2/173 (1.2) 0/139 (0.0) 1/184 (0.5) 3/504 (0.6)
Minor (protocol) 13/173 (7.5) 14/139(10.1) 21/184 (11.4) 48/504 (9.5)
Major (TIMI) 1/168 (0.6) 1/137 (0.7) 4/177 (2.3) 6/490 (1.2)
Minor (TIMI) 4/172 (2.3) 4/139 (2.9) 7/181 (3.9) 15/500 (3.0)
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► Bivalirudin, as the sole procedural anticoagulant, provided similar outcomes in all vessel types treated
► Consistent anticoagulation at the dose tested
► Major & minor hemorrhagic complications were low
► Times to sheath removal, ambulation, and discharge were favorable and appear to increase the potential for same-day discharge without compromising efficacy or safety
Summary:
APPROVE 30-day outcomes