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Local drug delivery devices for use in the vasculature
Local drug delivery devices for vessel
brupt estimated
closure, with
45 000
cases
a
an
year
worldwide, and restenosis, for which 150 000 revascularisation procedures are done, remain unsolved problems in interventional cardiology. At the second Local Drug over
Delivery Meeting held in Amsterdam (Feb 16-17), several new developments were presented. Systemic treatments for acute closure are expensive, and have not been proven to work for restenosis. In addition, the pathophysiology of restenosis no longer seems as simple as previously thought. It is related to arterial recoil, local thrombotic factors, myointimal hyperplasia, and arterial remodelling after injury. All these can be potentially tackled by local drug delivery. Juan Badimon (New York) discussed how "passivation" of arteries (reducing wall thrombogenicity) is after important angioplasty. Passivation can be enhanced by various agents, including direct thrombin inhibitors. Systemic administration of some of these, such as hirudin, are associated with haemorrhagic complications, so local delivery may enable a higher, more site-specific dose to be given without increasing side-effects. After angioplasty, platelets gather at the injury site. Electroporation, to encapsulate drugs within platelets (Neville Crawford, London), can be used to increase passivation. However, most local drug delivery methods for vascular disease are catheter-based and are designed to be used at
Restenosis rate
in whom a thrombus be seen either immediately before or after balloon angioplasty have a higher rate of restenosis at 6 months than do those in whom no thrombus was seen, according to a study by Dutch researchers. (Circulation 1996; 93: 889-97) The 2950 patients underwent coronary
angiography immediately
before angioplasty, immediately after angioplasty, and at 6 months. Patients who had an angiogram to assess symptoms before 4 months were
asked
to
undergo
a
repeat
procedure at 6 months. Of the 3583 lesions treated, thrombi were identified by angiography in 160. In those vessels with
thrombi,
the
in the vasculature
immediately after conventional angioplasty. Local drug delivery devices can deliver intraluminally (leaving drugs to diffuse into the wall), intramurally, or
into the adventitia. Choice of device depends on the duration of drug retention with each and on the targeted abnormality. In a n interesting study to compare retention of a coloured dye by four intraluminal delivery catheters, Charles Lambert (Alabama) used porcine carotid arteries, which have no large side branches where dye might leak, and are strong enough to work with. He found that, with all of these catheters, most of the dye is rapidly lost distally, leaving little where it is needed. Intramural delivery can be achieved by stents. Many varieties of stent design already exist in interventional cardiology, and these can be coated with active substances; novel or
biodegradable
stents
provide an are being
alternative method and
continually improved. The adventitia may play an important role in the pathology of restenosis (Andrew Zalewski, Philadelphia). Medial injury through angioplasty is known to lead to adventitial thicken-
ing. Moreover, tion
a
proliferative
reac-
be demonstrated in the adventitia, with production of extracellular matrix. This response is clearly important for determining the type of remodelling that the artery undergoes over time-whether it enlarges, allowing lumen preservation, or whether it shrinks, narrowing the artery and leading to restenosis.
higher when
Patients can
use
can
clot
seen at
time of
addition, Zalewski showed that myofibroblasts, which contribute to myointimal hyperplasia seem to migrate from the adventitia, a novel In
concept. Gene therapy can be applied locally with various delivery devices and in several animal models (Heiko von der Leyen, San Francisco; Sigrid Nikol, Munich). In man, the first gene-therapy project to be carried out in vascular disease is already yielding preliminary results. Patients with severe peripheral vascular disease were given the gene for vascular endothelial growth factor, an angio-
genic protein, intra-arterially. Angiography before and several months after local gene therapy showed that new
in
arterial collaterals had formed the treated limb (Takayuki
Asahara, Boston). Of the new devices many described at the meeting, perhaps the wildest was the pericardial sac delivery device (Keith March, Indianapolis). Designed to be screwed through the ventricular wall from the inside of the chamber, it deposits drug in the pericardial space to bathe the epicardial vessels. Although using the device to treat one lesion after angioplasty would probably be overkill, if the substance was active against a general component of atherosclerosis acting via the adventitia, adoption of the device might mean the end of angioplasty as done from within. Perhaps we will all require regular epicardial baths.
Tanya Y Huehns
angioplasty
restenosis rate was 43’1%, compared with 34’4% in those vessels in which thrombi were not seen (p<0’01; RR 1-449; CI 1-051-1-997). The higher restenosis rate was due primarily to an increased incidence of occlusion. The timing of the occlusion, however, is unclear, the researchers said. "If it occurred early, it is likely to have been the end result of an acute thrombotic process, whereas if it occurred late, it would be the final end result of the process of restenosis itself. We do not know when the occlusion at
follow-up angiography occurred in our patients, so our results must be speculative. We suspect, however,
that it occurred early." Their data, therefore, do not support the hypothesis that thrombi have a major role in the development of late myointimal hyperplasia, they said. Instead, local thrombus formation, in addition to causing acute occlusion, may also result in subacute occlusion. This suggests that treatments with monoclonal antibodies and synthetic peptides against the platelet glycoprotein IIb/IIIa receptor may derive some of their perceived clinical benefit by eliminating subacute occlusion without necessarily affecting the restenosis process. Michael McCarthy
679
brupt estimated
closure, with
45 000
cases
a
an
year
worldwide, and restenosis, for which 150 000 revascularisation procedures are done, remain unsolved problems in interventional cardiology. At the second Local Drug over
Delivery Meeting held in Amsterdam (Feb 16-17), several new developments were presented. Systemic treatments for acute closure are expensive, and have not been proven to work for restenosis. In addition, the pathophysiology of restenosis no longer seems as simple as previously thought. It is related to arterial recoil, local thrombotic factors, myointimal hyperplasia, and arterial remodelling after injury. All these can be potentially tackled by local drug delivery. Juan Badimon (New York) discussed how "passivation" of arteries (reducing wall thrombogenicity) is after important angioplasty. Passivation can be enhanced by various agents, including direct thrombin inhibitors. Systemic administration of some of these, such as hirudin, are associated with haemorrhagic complications, so local delivery may enable a higher, more site-specific dose to be given without increasing side-effects. After angioplasty, platelets gather at the injury site. Electroporation, to encapsulate drugs within platelets (Neville Crawford, London), can be used to increase passivation. However, most local drug delivery methods for vascular disease are catheter-based and are designed to be used at
Restenosis rate
in whom a thrombus be seen either immediately before or after balloon angioplasty have a higher rate of restenosis at 6 months than do those in whom no thrombus was seen, according to a study by Dutch researchers. (Circulation 1996; 93: 889-97) The 2950 patients underwent coronary
angiography immediately
before angioplasty, immediately after angioplasty, and at 6 months. Patients who had an angiogram to assess symptoms before 4 months were
asked
to
undergo
a
repeat
procedure at 6 months. Of the 3583 lesions treated, thrombi were identified by angiography in 160. In those vessels with
thrombi,
the
in the vasculature
immediately after conventional angioplasty. Local drug delivery devices can deliver intraluminally (leaving drugs to diffuse into the wall), intramurally, or
into the adventitia. Choice of device depends on the duration of drug retention with each and on the targeted abnormality. In a n interesting study to compare retention of a coloured dye by four intraluminal delivery catheters, Charles Lambert (Alabama) used porcine carotid arteries, which have no large side branches where dye might leak, and are strong enough to work with. He found that, with all of these catheters, most of the dye is rapidly lost distally, leaving little where it is needed. Intramural delivery can be achieved by stents. Many varieties of stent design already exist in interventional cardiology, and these can be coated with active substances; novel or
biodegradable
stents
provide an are being
alternative method and
continually improved. The adventitia may play an important role in the pathology of restenosis (Andrew Zalewski, Philadelphia). Medial injury through angioplasty is known to lead to adventitial thicken-
ing. Moreover, tion
a
proliferative
reac-
be demonstrated in the adventitia, with production of extracellular matrix. This response is clearly important for determining the type of remodelling that the artery undergoes over time-whether it enlarges, allowing lumen preservation, or whether it shrinks, narrowing the artery and leading to restenosis.
higher when
Patients can
use
can
clot
seen at
time of
addition, Zalewski showed that myofibroblasts, which contribute to myointimal hyperplasia seem to migrate from the adventitia, a novel In
concept. Gene therapy can be applied locally with various delivery devices and in several animal models (Heiko von der Leyen, San Francisco; Sigrid Nikol, Munich). In man, the first gene-therapy project to be carried out in vascular disease is already yielding preliminary results. Patients with severe peripheral vascular disease were given the gene for vascular endothelial growth factor, an angio-
genic protein, intra-arterially. Angiography before and several months after local gene therapy showed that new
in
arterial collaterals had formed the treated limb (Takayuki
Asahara, Boston). Of the new devices many described at the meeting, perhaps the wildest was the pericardial sac delivery device (Keith March, Indianapolis). Designed to be screwed through the ventricular wall from the inside of the chamber, it deposits drug in the pericardial space to bathe the epicardial vessels. Although using the device to treat one lesion after angioplasty would probably be overkill, if the substance was active against a general component of atherosclerosis acting via the adventitia, adoption of the device might mean the end of angioplasty as done from within. Perhaps we will all require regular epicardial baths.
Tanya Y Huehns
angioplasty
restenosis rate was 43’1%, compared with 34’4% in those vessels in which thrombi were not seen (p<0’01; RR 1-449; CI 1-051-1-997). The higher restenosis rate was due primarily to an increased incidence of occlusion. The timing of the occlusion, however, is unclear, the researchers said. "If it occurred early, it is likely to have been the end result of an acute thrombotic process, whereas if it occurred late, it would be the final end result of the process of restenosis itself. We do not know when the occlusion at
follow-up angiography occurred in our patients, so our results must be speculative. We suspect, however,
that it occurred early." Their data, therefore, do not support the hypothesis that thrombi have a major role in the development of late myointimal hyperplasia, they said. Instead, local thrombus formation, in addition to causing acute occlusion, may also result in subacute occlusion. This suggests that treatments with monoclonal antibodies and synthetic peptides against the platelet glycoprotein IIb/IIIa receptor may derive some of their perceived clinical benefit by eliminating subacute occlusion without necessarily affecting the restenosis process. Michael McCarthy
679