The Library

The von Willebrand Inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy : a randomized trial

Tools

Markus, Hugh S., McCollum, C. (Charles), Imray, C. (Chris), Goulder, M. A., Gilbert, J. (Jim) and King, A. (Alice). (2011) The von Willebrand Inhibitor ARC1779 reduces cerebral embolization after carotid endarterectomy : a randomized trial. Stroke, Vol.42 (No.8). pp. 2149-2153. ISSN 0039-2499

Full text not available from this repository.

Official URL: http://dx.doi.org/10.1161/STROKEAHA.111.616649

Abstract

Background and Purpose-Inhibition of von Willebrand factor offers a novel approach to prevention of stroke and myocardial ischemia but has not yet been demonstrated to show efficacy on clinically relevant end points. ARC1779 is an aptamer that inhibits the prothrombotic function of von Willebrand factor by binding to the A1 domain of von Willebrand factor and thereby blocking its interaction with glycoprotein. Phase 1 studies suggest it inhibits platelet aggregation with less increase in bleeding than conventional antiplatelet agents. The effect of ARC 1779 on cerebral emboli immediately after carotid endarterectomy was investigated in a randomized clinical trial.

Methods-Patients undergoing carotid endarterectomy were randomized double-blind to ARC1779 or placebo administered intravenously. Transcranial Doppler recording, to detect cerebral embolic signals, was performed in the first 3 hours postoperatively. The primary end point was time to first embolic signals.

Results-Thirty-six patients were recruited, 18 in each arm. The Kaplan-Meier median time to first embolic signals was 83.6 minutes for ARC1779 compared with 5.5 minutes for placebo. Using Cox proportional hazards embolic signals occurred statistically significantly later on ARC1779 (P=0.007). Reduced embolic signals counts were correlated with inhibition of von Willebrand factor activity (P=0.03). Increased perioperative bleeding and anemia were seen with ARC1779.

Conclusions-von Willebrand factor inhibition reduces thromboembolism in humans. It may play a role in treatment of stroke and myocardial ischemia. The extent to which bleeding complications occur in nonoperated patients needs to be assessed in further studies.

Item Type:

Journal Article

Subjects:

R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
R Medicine > RM Therapeutics. Pharmacology

Divisions:

Faculty of Medicine > Warwick Medical School

Library of Congress Subject Headings (LCSH):

Von Willebrand factor, Blood coagulation factor VIII antibodies, Clinical trials, Cerebrovascular disease -- Prevention, Embolism -- Treatment, Endarterectomy, Transcranial Doppler ultrasonography

Journal or Publication Title:

Stroke

Publisher:

Lippincott Williams & Wilkins

ISSN:

0039-2499

Official Date:

August 2011

Dates:

Date	Event
August 2011	Published

Volume:

Vol.42

Number:

No.8

Page Range:

pp. 2149-2153

Identification Number:

10.1161/STROKEAHA.111.616649

Status:

Peer Reviewed

Publication Status:

Published

Access rights to Published version:

Restricted or Subscription Access

Funder:

Archimex Corp.

References:

1. Rothwell PM, Buchan A, Johnston SC. Recent advances in management
of transient ischaemic attacks and minor ischaemic strokes. Lancet
Neurol. 2006;5:323–331.
2. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of
randomised trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ. 2002;324:71– 86.
3. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus
dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin
(ESPRIT): randomised controlled trial. Lancet. 2006;367:1665–1673.
4. Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, et al.
Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic
carotid stenosis evaluated using Doppler embolic signal detection: the
Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid
Stenosis (CARESS) trial. Circulation. 2005;111:2233–2240.
5. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan
AM. Fast assessment of stroke and transient ischaemic attack to prevent
early recurrence (FASTER): a randomised controlled pilot trial. Lancet
Neurol. 2007;6:961–969.
6. Wong KS, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN et al.
Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in
patients with acute symptomatic cerebral or carotid artery stenosis
(CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet
Neurol. 2010;9:489–497.
7. Geeganage C, Wilcox R, Bath PM. Triple antiplatelet therapy for preventing
vascular events: a systematic review and meta-analysis. BMC
Med. 2010;8:36.
8. Kleinschnitz C, De Meyer SF, Schwarz T, Austinat M, Vanhoorelbeke K,
Nieswandt B, et al. Deficiency of von Willebrand factor protects mice
from ischemic stroke. Blood. 2009;113:3600 –3603.
9. Gilbert JC, DeFeo-Fraulini T, Hutabarat RM, Horvath CJ, Merlino PG,
Marsh HN, et al. First-in-human evaluation of anti von Willebrand factor
therapeutic aptamer ARC1779 in healthy volunteers. Circulation. 2007;
116:2678 –2686.
10. Spiel AO, Mayr FB, Ladani N, Wagner PG, Schaub RG, Gilbert JC et al.
The aptamer ARC1779 is a potent and specific inhibitor of von Willebrand
factor mediated ex vivo platelet function in acute myocardial
infarction. Platelets. 2009;20:334 –340.
11. Markus HS, MacKinnon A. Asymptomatic embolization detected by
Doppler ultrasound predicts stroke risk in symptomatic carotid artery
stenosis. Stroke. 2005;36:971–975.
12. King A, Markus HS. Doppler embolic signals in cerebrovascular disease
and prediction of stroke risk: a systematic review and meta-analysis.
Stroke. 2009;40:3711–3717.
13. Levi CR, O’Malley HM, Fell G, Roberts AK, Hoare MC, Royle JP, et al.
Transcranial Doppler detected cerebral microembolism following carotid
endarterectomy. High microembolic signal loads predict postoperative
cerebral ischaemia. Brain. 1997;120:621– 629.
14. Payne DA, Jones CI, Hayes PD, Thompson MM, London NJ, Bell PR,
et al. Beneficial effects of clopidogrel combined with aspirin in
reducing cerebral emboli in patients undergoing carotid endarterectomy.
Circulation. 2004;109:1476 –1481.
15. Kaposzta Z, Baskerville PA, Madge D, Fraser S, Martin JF, Markus
HS. L-arginine and S-nitrosoglutathione reduce embolization in
humans. Circulation. 2001;103:2371–2375.
16. Kaposzta Z, Martin JF, Markus HS. Switching off embolization from
symptomatic carotid plaque using S-nitrosoglutathione. Circulation.
2002;105:1480 –1484.
17. Ringelstein EB, Droste DW, Babikian VL, Evans DH, Grosset DG, Kaps
M, et al. Consensus on microembolus detection by TCD. International
Consensus Group on Microembolus Detection. Stroke. 1998;29:725–729.
18. Markus HS, Molloy J. Use of a decibel threshold in detecting Doppler
embolic signals. Stroke. 1997;28:692– 695.
19. Andersen PK, Gill RD. Cox’s regression model for counting processes: a
large sample study. Ann Stat. 1982;10:1100 –1120.
20. Markus HS, Brown MM. Differentiation between different pathological
cerebral embolic materials using transcranial Doppler in an in vitro
model. Stroke. 1993;24:1–5.
21. Lee JF, Stovall GM, Ellington AD. Aptamer therapeutics advance. Curr
Opin Chem Biol. 2006;10:282–289.