Intra-arterial Thrombolysis in Peripheral

Arterial and Graft Occlusions

Flavio Castañeda, MD
Clinical Professor of Radiology and Surgery
University of Illinois College of Medicine at Peoria

Flavio Castaneda, MD
 Surgical Thrombectomy
• Harvey 1628 1° describe vascular occlusions
• Labey 1911 1° surgical embolectomy
• Murphy &
Brown 1938 1° to use heparin post-op
• Fogarty 1963 1° catheter embolectomy

Flavio Castaneda, MD
 Lower Extremity Ischemia
• Immediate surgical intervention is associated with major
morbidity and mortality in a high proportion of patients
with limb-threatening ischemia
• Blaisdell’s landmark study (1978):
– Over 3000 pts in 30 centers, 1963-1978 compilation
– Death in 30% of patients, amputation in 25% of survivors
• Today:
– Mortality rates remain over 10% for patients
with true limb-threatening ischemia
Flavio Castaneda, MD
 History of Thrombolysis
17 pts ( PE, DVT, Art. & SVF)
1-18 million u up to 80 hours
1972 IV SK Dotter
1974 IA SK Dotter 17(1/100
(Art.) 1-10,000 units/hr
IV dose
Failures 65%
1981 IA SK Bleeding 25% Katzen
1982 IA SK & UK Totty
1983 IA SK & UK Becker 93 (Art.) 120,000u/hr
1985 IA UK McNamara advancing cath.
Bolus 250,000u
1991 IA 2 doses UK Cragg 125,000/hr 50,000 u/hr
advancing cath.Flavio Castaneda, MD
 History of Thrombolysis
•Lower mortality
• Topas I
•Lower amputation
• Topas II
• Rochester •Lesser surgical magnitude

• Stile •Better event free survival @ 12 mos

• Purpose •Increase cost
•Increase bleeding with thrombolytics

Flavio Castaneda, MD
 History of Thrombolysis
Urokinase
• Predictable outcomes
• Excellent safety profile---Low ICH rate ≈0-2.1%
• 24-72 hour infusions
• Amputation-free survival ≈83-90% @ 30d
• Major hemorrhage rates ≈11-23%
• Facilitated adjunctive percutaneous interventions
• Lesser surgical interventions
Topas I & II,Rochester,STILE, & PURPOSE

Flavio Castaneda, MD
 History of Thrombolysis
Urokinase

• Defacto “off -label” standard of care

for Vascular Thrombolysis

Flavio Castaneda, MD
 History of Thrombolysis
• Removed by the FDA in January 1999
• Lytic agents available in the US
– Streptokinase - Streptase®, SK
– Tenecteplase - TNKase™, TNK-tPA
– Anistreplase - Eminase®, APSAC
– Alteplase - Activase®, rt-PA
– Reteplase - Retavase®, r-PA

Flavio Castaneda, MD
Semba JVIR 02/00

Flavio Castaneda, MD
 UK vs rt-PA:
Cleveland Clinic Experience

UK (N=483) rt-PA (N=144) p Value

Bleeding Requiring Transfusion 60 (12.4%) 32 (22.2%) 0.004

Hematoma 106 (21.9%) 63 (43.8%) <0.001
False Aneurysm 8 (1.7%) 4 (2.8%) N.S.
Intracranial Bleeding 3 (0.6%) 4 (2.8%) 0.031
Death 13 (2.7%) 6 (4.2%) N.S.

Ouriel JVIR 3/00

Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology: rt-PA (OSF experience)

• 70 pts with 74 limbs

• Lower extremity only
• Hx of acute change in symptoms
• Pts treated from 1/99 - 11/99
• Swischuk JVIR 4/01

Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology: rt-PA (OSF experience)
• Results
– Thrombolytic success - 86%
– Mean duration of infusion - 27.9 hrs
– Major hemorrhage - 27%
– Transfusions - 21%
– Amputation rate (30d) - 6%
– Death rate (30d) - 1%
– Amputation free survival (30d) - 93%
Flavio Castaneda, MD
Thrombolysis in Interventional
Radiology: rt-PA (OSF experience)

Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology: rt-PA (OSF experience)

Low Dose Protocol

• 29 pts with 29 limbs
• lower extremity only
• Similar technique except;
– Decreased dose rate to 0.5 mg/hr
– Decreased heparin dose (300 - 500 U/hr)
Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology: rt-PA (OSF experience)
• Results
– Thrombolytic success - 87%
– Mean duration of infusion 35.9 hr ( vs. 27.9 hr )
– Major bleeding - 10% (vs high dose 27%, p<0.05)
– Transfusion - 10% (vs high dose 21%, p<0.05)
– Amputation rate (30d) - 7%
– Death rate (30d) - 0%
– Amputation free survival (30d) - 93%
Flavio Castaneda, MD
 Thrombus Formation and Lysis
Extrinsic Pathway Intrinsic Pathway

Factors Xa and Va
a2-antiplasmin
Prothrombin Platelets
Plasminogen
+
Fibrin
Thrombin
PAI-1
Plasmin
Fibrinogen Fibrin Plasminogen Activator
Split endogenous or exogenous
Products UK, t-PA or reteplase
Flavio Castaneda, MD
 Classification of Fibrinolytics

rt-PA molecule
w/ 5 domains
•Finger
•EGF
•Kringle 1
•Kringle 2
•Protease

Flavio Castaneda, MD
 Classification of Fibrinolytics
t-PA Domain Function

Fibronectin finger High-affinity fibrin binding

Epidermal Binds hepatic receptors,

growth factor accelerating clearance

Kringle-1 Receptor binding

Kringle-2 Fibrin specificity

Protease Activates plasminogen

Carbohydrate Accelerates clearance Flavio Castaneda, MD

 Molecular Structures of
Urokinase, Alteplase, and Reteplase
1st Generation 2nd Generation 3rd Generation
Urokinase Alteplase Reteplase
Kringle 1 Kringle 2 Kringle 2
NH2
COOH EGF
Finger
NH2 * NH2

*
* NH2COOH
COOH COOH
Protease Protease

Flavio Castaneda, MD
 Pharmacology
Urokinase Alteplase Reteplase
Native protein Recombinant Recombinant
(glycosylated) (glycosylated) (non-glycosylated)

Plasma Half-life 15 min < 5 min 13-16 min

Affinity for Fibrin Low High Low
Fibrin Specificity Low High High
Thrombolytic Moderate High High
Efficacy*
Clot Penetration Unknown No Yes
*These rankings are factors of doses used in the clinical setting and may be a dose-dependent result.
Adapted with permission from Smalling RW, Hanna GP. In: Califf RM, ed. Thrombolytic Therapy: New Standards of Care: Part 1.
Am J Cardiol. 1996:9-15. Adapted with permission from Weaver WD. Eur Heart J. 1996;17(suppl F):9-15.
Martin U. Cardiovascular Drug Reviews. 1993, 11 (3): 299-311
Flavio Castaneda, MD
 Thrombolysis and Fibrin Affinity
Surface Fibrin Plasmin Fibrin
(Fibrin-associated) Degradation
Products
Plasminogen
(Fibrin-associated) Plasmin
CLOT

Plasminogen
Activator
Internal Fibrin
Plasminogen Plasmin
(Fibrin-associated) (Fibrin-associated)

Fibrin Fibrin
Degradation
Flavio Castaneda, MD
Products
Thrombolytic Therapy in the Treatment
of Acute Lower Extremity Arterial
Occlusions

Flavio Castaneda, MD
 Reteplase Arterial Study
Methodology
• Search for the ideal thrombolytic dose of Reteplase
that would maximize the benefit with the minimal
risk of bleeding
• IRB to prospectively collect data
• Prospective non-randomized study evaluating 3
decreasing dosing regimens in chronological order
• Patient enrollment from 4/1/00 to 6/21/01

Flavio Castaneda, MD
 Reteplase Arterial Study
Methodology

• Computerized database was created to allow

timely data entry and query results at any time
• Methodology: same as other studies
• All Pts received sub-Tx Heparin (400-500 u/hr)

Flavio Castaneda, MD
Flavio Castaneda, MD
 Reteplase Arterial Study
From 4/1/00 to 6/21/01

30 pts 37 pts 34 pts

0.5u/hr 0.25u/hr 0.125u/hr

Flavio Castaneda, MD
 Reteplase Arterial Study
Patient Demographics
0.5u/hr 0.25u/hr 0.125u/hr

Mean Age (yr) 69.47 66.41 67.15

(+ 12.16) (+ 13.53) (+ 10.91)

Male 14 (47%) 19 (51%) 20 (59%)

Female 16 (53%) 18 (49%) 14 (41%)

Flavio Castaneda, MD
 Reteplase Arterial Study
Co-morbidities*
0.50u/hr 0.25u/hr 0.125u/hr

Smoking 20 (67%) 23 (62.2%) 20 (58.8%)

CAD 14 (47%) 15 (40.5%) 5 (14.7%)
CHF 4 (13%) 3 (8.1%) 1 (2.9%)
Arrhythmias 5 (17%) 2 (5.4%) 2 (5.9%)
Hypertension 20 (67%) 19 (51.4%) 16 (47.1%)
Cholesterol 11 (37%) 8 (21.6%) 11 (32.4%)
Diabetes 8 (37%) 7 (18.9%) 11 (32.4%)
TIA 0 (0%) 0 (0%) 0 (0%)
COPD 4 (13%) 5 (13.5%) 4 (11.8%)
*No Statistical Differences Flavio Castaneda, MD
 Reteplase Arterial Study
0.50u/hr 0.25u/hr 0.125u/hr
Native Artery 10 (33%) 17 (45.9%) 13 (38.2%)

Bypass Graft 20 (67%) 20 (54.1%) 21 (61.8%)

Synthetic 17 (85.7%) 17 (85.7%) 15 (71.4%)
Vein 1 (4.8%) 0 (0%) 6 (28.6%)*
Composite 2 (9.5%) 3 (14.3%) 0 (0%)

*P < .05
Flavio Castaneda, MD
 Reteplase Arterial Study
0.5u/hr 0.25u/hr 0.125u/hr

Thrombus 29 (97%) 37 (100%) 33 (97.1%)

Embolus 1 (3%) 0 (0%) 1(2.9%)

Flavio Castaneda, MD
 Reteplase Arterial Study
0.5u/hr 0.25u/hr 0.125u/hr
Duration of
Symptoms 8.44 14.05 16.91
(days) (+8.03) (+20.94) (+23.61)
SVS/ISCVS Class
I 63.3% 81.1 % 79.4 %
II a 20.0 % 13.5 % 20.6 %
II b 16.7 % 5.4 % 0.0 %

Flavio Castaneda, MD
 Reteplase Arterial Study
Success Rate*

0.5u/hr 0.25u/hr 0.125u/hr

86.7% 83.8% 85.3%

* 95% thrombolysis with return antegrade flow (TIMI II-III)

Flavio Castaneda, MD
 Reteplase Arterial Study
Percutaneous Interventions After Thrombolysis
0.5u/hr 0.25u/hr 0.125u/hr
n=21/30 n=26/37 n=20/34

Stent Placement 4 (13.3%) 5 (13.5%) 1 (2.9%)

Angioplasty 17 (56.7%) 21 (56.8%) 19 (55.9%)

Flavio Castaneda, MD
 Reteplase Arterial Study
Surgical Procedures After Thrombolysis

0.5u/hr 0.25u/hr 0.125u/hr

n=5/30 n=6/37 n=1/34

New Graft 1 ( 3.3%) 0 0

Revision- 4 (13.3%) 6 (16.2%) 2 (5.8%)

Endarterectomy
Flavio Castaneda, MD
 Reteplase Arterial Study
0.5u/hr 0.25u/hr 0.125u/hr

Total infusion 28.38 hrs 30.65 hrs 42.13 hrs*

time (hrs) (+ 14.11) (+ 11.18) (+ 17.62)

**Total dose 14.16 9.22 6.03

used (u) (+ 7.14) (+ 5.95) (+ 2.92)

*p=<.001
**p=<.001
Flavio Castaneda, MD
 Reteplase Arterial Study
30-day amputation free survival rate

0.5u/hr 0.25u/hr 0.125u/hr

90% 97.3% 91.2%

Flavio Castaneda, MD
 Reteplase Arterial Study
Major Bleeding Complications*
0.5u/hr 0.25u/hr 0.125u/hr

Major* n=4 n=2 n=1

13.3%* 5.4% 2.9%

* Modified TIMI (PURPOSE trial) = Any hemorrhage leading to surgery,

extended hospitalization or transfusion

*P<.05
Flavio Castaneda, MD
 Reteplase Arterial Study
Results

• Intracerebral hemorrhage 0.99% (n=1)

– 70 (F) s/p failed surgical embolectomy and SK

infusion requiring a new fem-pop bypass 1 month
prior this admission. 0.5u/hr x 41 hrs -- ICH Alive
with deficit

Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology
67 y/o female with acute onset of left leg pain
and return of claudication

Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology
F/U angiograms after r-PA infusion at .125 U/hr

Distal
anastamosis
Prox thrombus
anastamosis

24 hr.s 48 hr.s Flavio Castaneda, MD

 Conclusions

• Success rate is similar for all groups

• The 0.50u/hr group is associated with
higher major bleeding complications
(13.3 vs 5.4 vs 2.9% )
• No statistical differences in infusion times
amongst the 0.50 and 0.25 groups
Flavio Castaneda, MD
 Conclusions

• The infusion time of the 0.125 group is 1/3

higher (42 vs 30 hrs) than the other two groups
- NOT related to ↑ vein grafts ( 29% vs ≤ 5%)
• No statistical differences in the 30-day
amputation rates between all groups

Flavio Castaneda, MD
 Conclusion Summary

• We feel that Reteplase at 0.25 u/hr

maximizes thrombolytic efficacy with an
acceptable major bleeding rate (5.4%).
• The 0.125 u/hr dose has a lower mayor
bleeding rate (2.9 vs 5.4%) but leads to
significantly longer infusions (≈30 vs 42hrs)
Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology
• What’s on the horizon?
– Mechanical thrombolysis?
– Adjunctive therapy - rapid lysis
• Mechanical - AJILE
• Pharmacological - glycoprotein IIb/IIIa inhibitors ,
RELAX, R&R

Flavio Castaneda, MD
Overview of Mechanical Thrombectomy Devices

Cordis-Hydrolyzer System

Flavio Castaneda, MD
Overview of Mechanical Thrombectomy Devices

Possis-AngioJet Single-Use Pump Set

Drive Unit

Family of Catheters

Flavio Castaneda, MD
Overview of Mechanical Thrombectomy Devices
Vortex non-Suction
Microvena-Amplatz/Helix Device

Helix impeller

Current
impeller

Flavio Castaneda, MD
Overview of Mechanical Thrombectomy Devices
Clot Macerators
Arrow-Trerotola Device

Flavio Castaneda, MD
 Overview of Mechanical Thrombectomy Devices
Clot Macerators
MTI-Castañeda Over-the-Wire Brush

Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology
• What’s on the horizon?
– Mechanical thrombolysis?
– Adjunctive therapy - rapid lysis
• Mechanical - AJILE
• Pharmacological - glycoprotein IIb/IIIa inhibitors ,
RELAX, R&R

Flavio Castaneda, MD
 Thrombolysis in Interventional
Radiology

• What’s on the horizon?

– Mechanical thrombolysis?
– Adjunctive therapy - rapid lysis
• Mechanical - AJILE
• Pharmacological - glycoprotein IIb/IIIa inhibitors ,
RELAX, R&R

Flavio Castaneda, MD
GP IIb/IIIa Receptor Blockade in
Peripheral Vascular Intervention: Rationale

• Underlying pathophysiology of PVD is atherosclerosis

• Plaque rupture (spontaneous or due to vascular
intervention) is a potent stimulus for platelet activation
and aggregation
• Coagulation system is activated by vessel damage and
activated platelets generate thrombin

Flavio Castaneda, MD
Flavio Castaneda, MD
 Platelet Adhesion and Activation
GPIIb/llla
GPIb/IX
Endothelium
von Willebrand
GPIa/IIa Factor

Collagen Fibrinogen or
Activation von Willebrand Factor

GPIIb/llla
Platelet Aggregation
Fibrinogen or ..
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von Willebrand Factor GPIIb/llla

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55
Flavio Castaneda, MD
 Passivation Following Vessel Injury

• Transition from a highly platelet reactive (thrombogenic)

to a non-reactive (non-thrombogenic) surface
• ~8 hours following injury of normal arteries
(Wilentz 1987; Groves 1986)
• Days to weeks following injury of atherosclerotic arteries
(Coller 1997)

Flavio Castaneda, MD
 Dethrombosis of Left Anterior Descending
Coronary Artery with Abciximab

Initial Angiogram Angiogram Post Abciximab Bolus

Flavio Castaneda, MD
Adapted with permission from Rerkpattanapipat P et al. Circulation. 1999;99:2965.
 Thrombolysis in Interventional
Radiology
• Conclusions
– Thrombolysis remains mainstay for the Tx of acute
peripheral arterial occlusion
– New agents are different than UK
– Difficult to predict results in peripheral system
from coronary data
– Bleeding remains the most significant complication
even with more fibrin specific agents
Flavio Castaneda, MD