ANNALS OF EMERGENCY MEDICINE
JULY 2015
Systematic Review Snapshot TAKE-HOME MESSAGE Glycoprotein IIb/IIIa inhibitors should be avoided in persons with acute ischemic stroke. METHODS
Do Glycoprotein IIb/IIIa Inhibitors Improve Outcomes in Acute Ischemic Stroke? EBEM Commentator
DATA SOURCES The authors searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and major ongoing trials, from 1966 through June 2013. References of included studies were manually searched, and contact was made with trial authors and pharmaceutical companies. The google.co.uk search engine was also manually searched to identify any further published or unpublished trials. In addition, the following international trial registries were also searched: Stroke Trials registry, clinicaltrials.gov, EU Clinical Trials Register, Current Controlled Trials, and World Health Organization International Clinical Trials Registry Platform. No language restriction was applied.
Latha Ganti, MD, MS North Florida South Georgia Veterans Affairs Medical Center Lake City, FL
Results Main results. Study, Year
n
Abciximab in Ischemic Stroke,1 2000 AbESTT,2 2005
74
400
AbESTT II/primary,3 2008 AbESTT II/ companion,3 2008 AbESTT/wake-up,4 2008
439
SETIS,5 2010
150
319
Agents
Inclusion
Outcomes, mRS Score
Results
Abciximab/ AIS 14
>2
OR¼0.30; 95% CI 0.03–2.8
Abciximab/ AIS 2
OR 1.00, 95% CI 0.5–1.9
Total n 1,365
STUDY SELECTION Randomized clinical trials of glycoprotein IIb/IIIa inhibitors in patients of any age with ischemic stroke of 6 hours onset or less. The trials could compare glycoprotein IIb/IIIa inhibitors with placebo, with open control, with recombinant tissue plasminogen activator, or in combination with recombinant tissue plasminogen activator compared with recombinant tissue plasminogen activator alone.
Volume 66, no. 1 : July 2015
AIS, Acute ischemic stroke; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; OR, odds ratio; CI, confidence interval; AbESTT, Abciximab in Emergent Stroke Treatment Trial; AbESTT II, Abciximab in Emergent Stroke Treatment Trial II; SETIS, Study of Efficacy of Tirofiban in acute Ischaemic Stroke.
Commentary Acute ischemic stroke is a true medical emergency, and pharmacologic interventions have by and large been patterned after treatments for acute myocardial infarction. The use of glycoprotein IIb/ IIIa inhibitors is no different, and the current review, including only randomized trials with low risk of bias, unfortunately suggests that
glycoprotein IIb/IIIa inhibitors appear to increase morbidity in acute ischemic stroke, without evidence of benefit. Research using glycoprotein IIb/ IIIa inhibitors for acute ischemic stroke has been ongoing for more than 15 years, with the first clinical trial results published in 2000.1 These early data appeared promising, with a trend toward Annals of Emergency Medicine 65
Systematic Review Snapshot DATA EXTRACTION AND SYNTHESIS Authors independently selected trials for inclusion and assessed trial quality according to various possible biases, including selection, performance, detection, attrition, and reporting bias, with each bias type given a “risk category” of unclear, low, medium, or high. There was no significant heterogeneity in trial results, allowing pooled statistical reporting.
improvement on the modified Rankin Scale despite increased intracranial hemorrhage. The subsequent AbESTT2 trial also reported a trend toward increased ICH and improved functional outcomes with abciximab. This paved the way for
66 Annals of Emergency Medicine
the much larger AbESTT II,3 which was terminated early because of harms related to ICH. Given the lack of benefit and the significantly increased risk of bleeding, glycoprotein IIb/IIIa inhibitors cannot be recommended for acute ischemic stroke. Moreover, the rate of harms appears high enough that future trials investigating their use in stroke are unlikely. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review is: Ciccone A1, Motto C, Abraha I, et al. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:
CD005208. http://dx.doi.org/10. 1002/14651858.CD005208.pub3. 1. Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose escalation study. Stroke. 2000;31:601-609. 2. Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke. 2005;36:880-890. 3. Adams HP, Effron MB, Torner J, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial. Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke. 2008;39:87-99. 4. Adams HP, Leira EC, Torner J, et al. Treating patients with “wake-up” stroke: the experience of the AbESTT-II trial. Stroke. 2008;39:3277-3282. 5. Torgano G, Zecca B, Monzani V, et al. Effect of intravenous tirofiban and aspirin in reducing short-term and long-term neurologic deficit in patients with ischemic stroke: a double-blind randomized trial. Cerebrovasc Dis. 2010;29:275-281.
Volume 66, no. 1 : July 2015
JULY 2015
Systematic Review Snapshot TAKE-HOME MESSAGE Glycoprotein IIb/IIIa inhibitors should be avoided in persons with acute ischemic stroke. METHODS
Do Glycoprotein IIb/IIIa Inhibitors Improve Outcomes in Acute Ischemic Stroke? EBEM Commentator
DATA SOURCES The authors searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and major ongoing trials, from 1966 through June 2013. References of included studies were manually searched, and contact was made with trial authors and pharmaceutical companies. The google.co.uk search engine was also manually searched to identify any further published or unpublished trials. In addition, the following international trial registries were also searched: Stroke Trials registry, clinicaltrials.gov, EU Clinical Trials Register, Current Controlled Trials, and World Health Organization International Clinical Trials Registry Platform. No language restriction was applied.
Latha Ganti, MD, MS North Florida South Georgia Veterans Affairs Medical Center Lake City, FL
Results Main results. Study, Year
n
Abciximab in Ischemic Stroke,1 2000 AbESTT,2 2005
74
400
AbESTT II/primary,3 2008 AbESTT II/ companion,3 2008 AbESTT/wake-up,4 2008
439
SETIS,5 2010
150
319
Agents
Inclusion
Outcomes, mRS Score
Results
Abciximab/ AIS 14
>2
OR¼0.30; 95% CI 0.03–2.8
Abciximab/ AIS 2
OR 1.00, 95% CI 0.5–1.9
Total n 1,365
STUDY SELECTION Randomized clinical trials of glycoprotein IIb/IIIa inhibitors in patients of any age with ischemic stroke of 6 hours onset or less. The trials could compare glycoprotein IIb/IIIa inhibitors with placebo, with open control, with recombinant tissue plasminogen activator, or in combination with recombinant tissue plasminogen activator compared with recombinant tissue plasminogen activator alone.
Volume 66, no. 1 : July 2015
AIS, Acute ischemic stroke; NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale; OR, odds ratio; CI, confidence interval; AbESTT, Abciximab in Emergent Stroke Treatment Trial; AbESTT II, Abciximab in Emergent Stroke Treatment Trial II; SETIS, Study of Efficacy of Tirofiban in acute Ischaemic Stroke.
Commentary Acute ischemic stroke is a true medical emergency, and pharmacologic interventions have by and large been patterned after treatments for acute myocardial infarction. The use of glycoprotein IIb/ IIIa inhibitors is no different, and the current review, including only randomized trials with low risk of bias, unfortunately suggests that
glycoprotein IIb/IIIa inhibitors appear to increase morbidity in acute ischemic stroke, without evidence of benefit. Research using glycoprotein IIb/ IIIa inhibitors for acute ischemic stroke has been ongoing for more than 15 years, with the first clinical trial results published in 2000.1 These early data appeared promising, with a trend toward Annals of Emergency Medicine 65
Systematic Review Snapshot DATA EXTRACTION AND SYNTHESIS Authors independently selected trials for inclusion and assessed trial quality according to various possible biases, including selection, performance, detection, attrition, and reporting bias, with each bias type given a “risk category” of unclear, low, medium, or high. There was no significant heterogeneity in trial results, allowing pooled statistical reporting.
improvement on the modified Rankin Scale despite increased intracranial hemorrhage. The subsequent AbESTT2 trial also reported a trend toward increased ICH and improved functional outcomes with abciximab. This paved the way for
66 Annals of Emergency Medicine
the much larger AbESTT II,3 which was terminated early because of harms related to ICH. Given the lack of benefit and the significantly increased risk of bleeding, glycoprotein IIb/IIIa inhibitors cannot be recommended for acute ischemic stroke. Moreover, the rate of harms appears high enough that future trials investigating their use in stroke are unlikely. Editor’s Note: This is a clinical synopsis, a regular feature of the Annals’ Systematic Review Snapshot (SRS) series. The source for this systematic review is: Ciccone A1, Motto C, Abraha I, et al. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev. 2014;3:
CD005208. http://dx.doi.org/10. 1002/14651858.CD005208.pub3. 1. Abciximab in Ischemic Stroke Investigators. Abciximab in acute ischemic stroke: a randomized, double-blind, placebo-controlled, dose escalation study. Stroke. 2000;31:601-609. 2. Abciximab Emergent Stroke Treatment Trial (AbESTT) Investigators. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of a randomized phase 2 trial. Stroke. 2005;36:880-890. 3. Adams HP, Effron MB, Torner J, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial. Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke. 2008;39:87-99. 4. Adams HP, Leira EC, Torner J, et al. Treating patients with “wake-up” stroke: the experience of the AbESTT-II trial. Stroke. 2008;39:3277-3282. 5. Torgano G, Zecca B, Monzani V, et al. Effect of intravenous tirofiban and aspirin in reducing short-term and long-term neurologic deficit in patients with ischemic stroke: a double-blind randomized trial. Cerebrovasc Dis. 2010;29:275-281.
Volume 66, no. 1 : July 2015
