A randomised controlled trial of antiplatelet therapy in combination with Rt-PA thrombolysis in ischemic stroke: rationale and design of the ARTIS-Trial.
BACKGROUND
Thrombolysis with intravenous rt-PA is currently the only approved acute therapy for ischemic stroke. Re-occlusion after initial recanalization occurs in up to 34% in patients treated with rt-PA, probably caused by platelet activation. In acute myocardial infarction, the combination of thrombolysis and antiplatelet therapy leads to a greater reduction of mortality compared to thrombolysis alone. In patients with acute ischemic stroke, several studies showed that patients already on antiplatelet treatment prior to thrombolysis had an equal or even better outcome compared to patients without prior antiplatelet treatment, despite an increased risk of intracerebral bleeding. Based on the fear of intracerebral haemorrhage, current international guidelines recommend postponing antiplatelet therapy until 24 hours after thrombolysis. Remarkably, prior use of antiplatelet therapy is not a contra-indication for thrombolysis. We hypothesize that antiplatelet therapy in combination with rt-PA thrombolysis will improve outcome by enhancing fibrinolysis and preventing re-occlusion.


METHODS
ARTIS is a randomised multi-center controlled trial with blind endpoint assessment. Our objective is to investigate whether immediate addition of aspirin to rt-PA thrombolysis improves functional outcome in ischemic stroke. Patients with acute ischemic stroke eligible for rt-PA thrombolysis are randomised to receive 300 mg aspirin within 1.5 hours after start of thrombolysis or standard care, consisting of antiplatelet therapy after 24 hours. Primary outcome is poor functional health at 3 months follow-up (modified Rankin Scale 3 - 6).


CONCLUSIONS
This is the first clinical trial investigating the combination of rt-PA and acute aspirin by means of a simple and cheap adjustment of current antiplatelet regimen. We expect the net benefit of improved functional outcome will overcome the possible slightly increased risk of intracerebral haemorrhage.


BACKGROUND
The Netherlands National Trial Register NTR822. The condensed rationale of the ARTIS-Trial has already been published in Cerebrovascular Diseases.
Zinkstok
S M
SM
Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands. s.m.zinkstok@amc.uva.nl
Vermeulen
M
M
Stam
J
J
de Haan
R J
RJ
Roos
Y B
YB
D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D009426:Netherlands; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000627:therapeutic use; D012107:Research Design; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D001241:Aspirin
Cerebrovasc Dis. 2007;24(1):56-65
17519545
Stroke. 2005 Jul;36(7):1452-6
15947260
Cerebrovasc Dis. 2003;16(3):183-90
12865603
Stroke. 2001 Mar;32(3):661-8
11239184
Cerebrovasc Dis. 2008;26(2):126-33
18560215
Arch Neurol. 2008 May;65(5):607-11
18332238
Stroke. 2000 Jul;31(7):1555-60
10884453
Neurology. 2002 Sep 24;59(6):862-7
12297567
Circulation. 1997 Jun 3;95(11):2508-16
9184581
Health Qual Life Outcomes. 2005 Dec 29;3:83
16381611
Stroke. 2008 Dec;39(12):3316-22
18927461
N Engl J Med. 2008 Sep 25;359(13):1317-29
18815396
Stroke. 2006 Jul;37(7):1798-804
16763191
Cerebrovasc Dis. 2010;29(1):79-81
19907167
Lancet. 2007 Jan 27;369(9558):275-82
17258667
Lancet. 2004 Mar 6;363(9411):768-74
15016487
Lancet. 1988 Aug 13;2(8607):349-60
2899772
Stroke. 2001 Dec 1;32(12):2821-7
11739980
Circulation. 1999 Jun 15;99(23):3050-5
10368124
Lancet. 1995 Dec 9;346(8989):1509-14
7491044
Circulation. 2002 Apr 9;105(14):1679-85
11940547
Stroke. 1999 Oct;30(10):2101-4
10512913
Circulation. 2007 May 22;115(20):e478-534
17515473
Cochrane Database Syst Rev. 2003;(3):CD000213
12917889
Stroke. 2007 Jan;38(1):69-74
17138949
Stroke. 2007 May;38(5):1639-40
17379817
Clin Cardiol. 2000 Sep;23(9):697-700
11016021
N Engl J Med. 1995 Dec 14;333(24):1581-7
7477192
Stroke. 2007 Mar;38(3):967-73
17272772
Circulation. 1991 Jan;83(1):170-5
1898641
Circulation. 1993 Oct;88(4 Pt 1):1484-94
8403296