Citation bias favoring positive clinical trials of thrombolytics for acute ischemic stroke: a cross-sectional analysis.
BACKGROUND
Citation bias occurs when positive trials involving a medical intervention receive more citations than neutral or negative trials of similar quality. Several large clinical trials have studied the use of thrombolytic agents for the treatment of acute ischemic stroke with differing results, thereby presenting an opportunity to assess these trials for evidence of citation bias. We compared citation rates among positive, neutral, and negative trials of alteplase (tPA) and other thrombolytic agents for stroke.


METHODS
We used a 2014 Cochrane Review of thrombolytic therapy for the treatment of acute stroke to identify non-pilot, English-language stroke trials published in MEDLINE-indexed journals comparing thrombolytic therapy with control. We classified trials as positive if there was a statistically significant primary outcome difference favoring the intervention, neutral if there was no difference in primary outcome, or negative for a significant primary outcome difference favoring the control group. Trials were also considered negative if safety concerns supported stopping the trial early. Using Scopus, we collected citation counts through 2015 and compared citation rates according to trial outcomes.


RESULTS
Eight tPA trials met inclusion criteria: two were positive, four were neutral, and two were negative. The two positive trials received 9080 total citations, the four neutral trials received 4847 citations, and the two negative trials received 1096 citations. The mean annual per-trial citation rates were 333 citations per year for positive trials, 96 citations per year for neutral trials, and 35 citations per year for negative trials. Trials involving other thrombolytic agents were not cited as often, though as with tPA, positive trials were cited more frequently than neutral or negative trials.


CONCLUSIONS
Positive trials of tPA for ischemic stroke are cited approximately three times as often as neutral trials, and nearly 10 times as often as negative trials, indicating the presence of substantial citation bias.
Department of Emergency Medicine, Cooper Medical School of Rowan University, One Cooper Plaza, Suite 152, Camden, NJ, 08103, USA.
Benjamin S
BS
Misemer
Department of Emergency Medicine, University of North Carolina, Chapel Hill, 170 Manning Drive, CB#7594, Chapel Hill, NC, 27599, USA.
Timothy F
TF
Platts-Mills
Department of Emergency Medicine, Cooper Medical School of Rowan University, One Cooper Plaza, Suite 152, Camden, NJ, 08103, USA. Jones-christopher@cooperhealth.edu.
Christopher W
CW
Jones
Bias; Citation bias; Stroke; Tissue plasminogen activator
Ann Emerg Med. 2015 Sep;66(3):322-333.e31
26304253
BMJ. 2015 Mar 17;350:h1075
25786912
Stroke. 2005 Jan;36(1):66-73
15569863
Lancet. 2015 Jan 10;385(9963):117-71
25530442
Lancet. 1998 Oct 17;352(9136):1245-51
9788453
N Engl J Med. 1995 Dec 14;333(24):1581-7
7477192
Lancet. 1995 Dec 9;346(8989):1509-14
7491044
J Clin Epidemiol. 2013 Mar;66(3):296-301
23347853
N Engl J Med. 2008 Sep 25;359(13):1317-29
18815396
Lancet. 2012 Jun 23;379(9834):2352-63
22632908
JAMA. 1999 Dec 1;282(21):2003-11
10591382
Cochrane Database Syst Rev. 2014 Jul 29;(7):CD000213
25072528
JAMA. 1999 Dec 1;282(21):2019-26
10591384
Lancet Neurol. 2009 Feb;8(2):141-50
19097942
Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15316-21
25288774
JAMA. 2006 Jan 4;295(1):90-3
16391221
JAMA. 1996 Sep 25;276(12):961-6
8805730
Lancet Neurol. 2016 Aug;15(9):925-33
27289487
Stroke. 2000 Apr;31(4):811-6
10753980
Stroke. 2007 Oct;38(10):2633-9
17702958
Lancet. 2014 Nov 29;384(9958):1929-35
25106063
JAMA. 2002 Jun 5;287(21):2847-50
12038930
BMC Med. 2015 Jul 03;13:158
26141137
JAMA. 1995 Oct 4;274(13):1017-25
7563451
Control Clin Trials. 1996 Feb;17(1):1-12
8721797
N Engl J Med. 1996 Jul 18;335(3):145-50
8657211
BMJ. 2009 Jul 20;339:b2680
19622839
Lancet Neurol. 2008 Apr;7(4):299-309
18296121
Stroke. 2013 Mar;44(3):870-947
23370205
Trials. 2010 Apr 13;11:37
20388211
Cerebrovasc Dis. 2008;25(5):457-507
18477843