Circulation, Vol 90, 2474-2480, Copyright © 1994 by American Heart Association
BJ Meyer, A Fernandez-Ortiz, A Mailhac, E Falk, L Badimon, AD Michael, JH Chesebro, V Fuster and JJ Badimon
BACKGROUND--The major morbidity of percutaneous transluminal coronary
angioplasty is acute thrombosis and restenosis of the dilated lesion.
Platelet-thrombus deposition occurs within minutes after injury, is
primarily mediated by thrombin, causes acute occlusion, and contributes to
late restenosis. Experimentally, specific thrombin inhibitors have
prevented mural thrombosis. However, local therapy may be more effective
than systemic treatment. We tested the hypothesis that high local
concentrations of an antithrombin drug at the site of arterial injury
following balloon angioplasty inhibit platelet thrombus formation equally
or better than conventional systemic treatment and at lower systemic
anticoagulant levels. METHODS AND RESULTS--Balloon angioplasty of the
carotid arteries of 29 pigs was performed using systemic intravenous
treatment with heparin (100 U/kg, groups I and II), suboptimal r-hirudin
(0.3 mg/kg, group III), and higher-dose r- hirudin (0.7 mg/kg, group IV),
which is the lowest dose that completely inhibited arterial thrombosis in
the pig. Immediately after balloon angioplasty of the first carotid,
additional local therapy with placebo (group I) or r-hirudin (groups II,
III, and IV; 0.3 mg/kg in 1 mL) was administered with distal perfusion
through a new percutaneous double- balloon catheter. After 1 hour of local
drug delivery, angioplasty of the contralateral carotid was performed.
Reflow for 1 hour was permitted to both carotids to compare the short-term
effect of local plus systemic treatment with systemic treatment on
quantitative 111In- labeled platelet deposition and macroscopic mural
thrombus formation on deeply injured carotid segments. Local drug delivery
of placebo compared with systemic heparin treatment resulted in no change
of platelet deposition (x 10(6)/cm2, mean +/- SEM) in controls (group I,
91.0 +/- 23.5 versus 80.8 +/- 19.4), but local delivery of r-hirudin
resulted in a significant reduction in group II (15 +/- 2.5 versus 71.3 +/-
14.5; P < .02) and group III (11.4 +/- 2.5 versus 80.5 +/- 11.4; P <
.01) and was borderline in group IV (7.4 +/- 1.8 versus 14.1 +/- 7.4; P =
.05), respectively. The incidence of macroscopic mural thrombus formation
with local and systemic treatment was 86% and 75% in group I, 16% and 70%
in group II, 14% and 71% in group III, and 0% and 16% in group IV,
respectively. CONCLUSIONS--Local therapy with the specific thrombin
inhibitor r-hirudin significantly reduces short-term quantitative platelet
deposition and macroscopic mural thrombus formation following balloon
angioplasty compared with systemic treatment of conventional doses of
heparin and hirudin and requires a significantly smaller amount of the
recombinant drug.
ARTICLES
Local delivery of r-hirudin by a double-balloon perfusion catheter prevents mural thrombosis and minimizes platelet deposition after angioplasty
Cardiovascular Biology Research Laboratory, Massachusetts General Hospital, Boston.
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