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 » Introduction
 »  Materials and Me...
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ORIGINAL ARTICLE
Year : 2014  |  Volume : 62  |  Issue : 6  |  Page : 631-634

Combination therapy of intravenous glycoprotein IIB/IIIA inhibitors and tissue plasminogen activator for acute ischemic stroke


1 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, United State
2 Department of Cardiology, State University of New York Downstate Medical Center, New York, United State

Date of Submission17-Oct-2014
Date of Decision04-Dec-2014
Date of Acceptance21-Dec-2014
Date of Web Publication16-Jan-2015

Correspondence Address:
Divyanshu Dubey
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Harry Hines Blvd. Dallas, Texas
United State
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.149385

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 » Abstract 

Objectives: Retrospective pooled analysis of data from published prospective studies and randomized phase 1 and 2 trials was done to assess efficacy and safety profile of intravenous combination therapy [glycoprotein IIb/IIIa inhibitors and IV tissue plasminogen activator (tPA)] in management of acute ischemic stroke. Materials and Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, and EMBASE databases; two reviewers independently selected studies reporting safety endpoints and outcome measures in acute ischemic stroke patients treated with combination therapy. tPA arm of the National Institute of Neurological Disorders and Stroke (NINDS) tPA trial was included in tPA-only group. Weighted means and proportions were calculated for numeric and categorical variables respectively. Bivariate analysis using Fisher's exact test was done to compare baseline descriptors, safety endpoints, and outcome measures. Results: Combination therapy arm included 188 patients and IV tPA arm had 218 patients. Mean National Institutes of Health Stroke Scale (NIHSS) in two groups were 12.8 and 14.6, respectively. Mean time-to-treatment was 2.3 hours in combination therapy arm and 2.55 hours in tPA arm. Treatment with combination therapy was associated with significant reduction in rate of symptomatic intracranial hemorrhage (sICH) [odds ratio (OR) 0.26, 95% cumulative incidence (CI) 0.07 0.83, P value 0.01). Difference in better functional outcome at 90 days (OR 0.87, 95% CI 0.59-1.30, P value 0.54) and death at 90 days (OR 1.16, 95% CI 0.69-1.93, P value 0.60) were not significantly different in two groups. Conclusion: Combination of low dose IV TPA with glycoprotein IIb/IIIa inhibitors is associated with reduction in sICH rates in patients with acute ischemic stroke as compared to standard dose of IV tPA.


Keywords: Abciximab, eptifibatide, glycoprotein IIb/IIIa inhibitors, hemorrhage, stroke, thrombolysis, tissue plasminogen activator


How to cite this article:
Dubey D, Banerjee C, Sawhney A, Sharma A, Alberts MJ. Combination therapy of intravenous glycoprotein IIB/IIIA inhibitors and tissue plasminogen activator for acute ischemic stroke. Neurol India 2014;62:631-4

How to cite this URL:
Dubey D, Banerjee C, Sawhney A, Sharma A, Alberts MJ. Combination therapy of intravenous glycoprotein IIB/IIIA inhibitors and tissue plasminogen activator for acute ischemic stroke. Neurol India [serial online] 2014 [cited 2019 Nov 21];62:631-4. Available from: http://www.neurologyindia.com/text.asp?2014/62/6/631/149385



 » Introduction Top


Tissue plasminogen activator (tPA) causes reperfusion by breaking down the fibrin-rich clot obstructing circulation. [1] But at the same time, it can also lead to an increase in thrombin activity and platelet activation, leading to an increased risk of vascular re-occlusion. [2] Studies on patients with acute myocardial infarction have shown augmented rates of platelet activation after fibrinolysis, thereby predisposing to vessel re-occlusion in some cases. [2] Glycoprotein IIb/IIIa (GpIIb/IIIa) inhibitors block the platelet aggregation following fibrinolysis. [3] Hence, concomitant use of a GpIIb/IIIa inhibitor with tPA may be useful to prevent early vessel re-occlusion.

No large phase III randomized clinical trial has assessed the efficacy of combination therapy (GpIIb/IIIa inhibitor + IV tPA) versus standard of care (IV tPA alone) in acute ischemic stroke. We performed a retrospective pooled analysis of data from published prospective studies and randomized phase 1 and 2 trials to assess efficacy and safety profile of IV combination therapy (GpIIb/IIIa inhibitor and tPA) in the management of acute ischemic stroke.


 » Materials and Methods Top


We searched the Cochrane Stroke Group trials register, Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, and EMBASE databases, and selected studies reporting safety endpoints and outcome measures in acute ischemic stroke patients treated with tPA + GpIIb/IIIa inhibitor. We aimed to consider all randomized control trials and prospective studies (prospective cohort, or prospective case-control study) using combination therapy (tPA + GpIIb/IIIa inhibitor) in acute ischemic stroke.

Outcome measures

Safety

(1) Death: Number of deaths from any cause at the end of the follow-up and (2) symptomatic intracranial hemorrhage (sICH): Number of patients with intracranial hemorrhage (ICH) after administration of therapeutic agent (either combination therapy or tPA alone) leading to clinical deterioration or death, confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) or at post mortem autopsy.

Efficacy

Functional outcome at 3 months: Number of patients who were able to reach a level of functional ability to carry out their usual activities with or without symptoms at 3 months after administration of therapeutic agent (modified rank in scale less than 2).

Two independent authors selected the studies, assessed their quality, and extracted the data. Inter-observer variation was calculated using kappa statistics. Demographic/clinical variables included sex, age, National Institutes of Health (NIH) stroke scale (NIHSS) at presentation and time-to-treatment. sICH within 36 hours was used as the safety endpoint. Death and modified Rankin scale (mRS) 0-1 at 90 days were used to assess functional outcome in the two groups. Treatment (tPA) arm of the National Institute of Neurological Disorders and Stroke (NINDS) tPA trial was included in the tPA only group. Weighted means and proportions were calculated for numeric and categorical variables respectively. Bivariate analysis using Fisher's exact test was done to compare baseline descriptors, safety endpoints, and outcome measures.


 » Results Top


Four studies met pre-specified inclusion criteria for analysis [Table 1]. One hundred and eighty-eight patients comprised the combination therapy arm, whereas the IV tPA arm had 218 patients. Mean age of patients in the combination therapy group was 70.36 years and in the tPA alone group was 68.59 years. Mean NIHSS in the two groups were 12.8 and 14.6, respectively. Mean time-to-treatment was 2.3 hours in combination therapy arm and 2.55 hour in the tPA alone arm [Table 2]. Reduced dose of tPA in the combination therapy arm was 0.3-0.6 mg/kg, whereas standard dose of 0.9 mg/kg was used in tPA arm. Seventy-seven out of 188 patients (40.95%) in the combination therapy arm had a modified rank in scale 0-1 at 90 days as compared to 99 out of 218 patients (45.41%) in the tPA alone arm in the IV tPA alone arm (OR 0.87, 95% CI 0.59-1.30, P 0.54) at 90 days. Four out of 188 (2.13%) patients in the combination therapy arm, and 17 out of 218 (7.79%) patients in the tPA arm had sICH. There was a significant reduction in the rate of sICH (OR 0.26, 95% CI 0.07-0.83, P value 0.01) in the combination therapy group. Death at 90 days was not significantly different in the two groups (OR 1.16, 95% CI 0.69-1.93, P value 0.60).
Table 1: Clinical and demographic characteristics of studies included

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Table 2: Clinical and demographic variables in CT and tPA arms

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 » Discussion Top


Our pooled analysis of this data showed that functional outcome at 90 days was not significantly different in the two groups (OR 0.87, 95% CI 0.59-1.30, P 0.54). There was a reduction in the rate of sICH (OR 0.26, 95% CI 0.07-0.83) with use of combination therapy. No significant difference was found in mortality at 90 days.

Thrombolytic-mediated fibrinolysis of the clot causes release of thrombin and platelet activation. Heightened thrombin activity leads to increased expression of GPIIb/IIIa receptors on the surface of platelets and subsequent formation of cross linkages by ligands such as fibrinogen. [4] As platelets are activated, the clot becomes resistant to lysis because of clot contraction from the release of plasminogen activator inhibitor-1 (PAI-1). [4],[5] Adhesion of platelets to the inner vessel walls leads to activation of matrix metalloproteinase, which can promote hemorrhagic transformation. Thus, the use of GpIIb/IIIa inhibitors may prevent degradation of micro-vessel thereby reducing the rate of sICH as well. [5],[6]

In the NINDS trial, 13% patients showed some clinical deterioration after tPA use in the absence of any intracranial hemorrhage. [1],[5] A subsequent study showed that 34% of those treated with IV tPA have early reocclusion, which was thought to explain deterioration after tPA in two thirds of patients. [7] In another study by Rubiera et al., 25% of study participants who achieved middle cerebral artery (MCA) recanalization following IV tPA administration had clinical deterioration after initial improvement. Seventeen of these 21 patients had demonstrable re-occlusion on transcranial doppler imaging. [8]

This phenomenon may be reduced with the use of a GpIIb/IIIa inhibitor. The GpIIb/IIIa receptor antagonists selectively inhibit the platelet integrin a IIb B III fibrinogen receptor and thereby inhibit adenosine diphosphate (ADP)-induced platelet aggregation. [8] Experimental animal studies have demonstrated that infusion of GPIIb/IIIa inhibitors prevents platelet accumulation in microvasculature and significantly reduces the infarct size. [9] Use of combination therapy in mice has been shown to increase efficiency of clot dissolution and reduce infarct size. [10] Concomitant use of GPIIb/IIIa inhibitors with tPA may improve thrombolytic entry into the thrombus. [11],[12] Another benefit of combination therapy might be prevention of downstream platelet micro-emboli that have been observed in animal models of thrombolysis. [13] It is also hypothesized that the rate of re-occlusion following the use of combination therapy would be decreased. [11]

Use of combination therapy of GpIIb/IIIa inhibitor with a reduced dose of IV tPA (tier 1 0.30 mg/kg and tier 2 0.45 mg/Kg) was compared with standard tPA dose in Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke trial (CLEAR trial). [14] Despite older age and higher baseline stroke severity in the combination treatment group, the rate of symptomatic ICH (1% versus 8%) and any ICH (10.3% versus 12%) were lower in combination therapy arm, although this was only a trend and not a statistically significant difference. [14] Subsequently, Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial evaluated increased tPA dose (0.6 mg/kg, lower than standard tPA dose) in the combination therapy. [15] There was a reduction in the rate of symptomatic ICH in the combination arm compared to the control standard tPA arm (OR, 0.15; 95% CI, 0.01-1.40; P = 0.053). There was also a trend towards improved functional outcome (mRS 0-1) at 3 months (OR, 1.74; 95% CI, 0.70-4.31; P = 0.23). [15] Few small non-randomized case series have also been published demonstrating safety and efficacy of combination therapy in acute stroke. [16],[17] Results of our retrospective pooled analysis are in consensus with a recent study which reported an absolute risk reduction of 6% in a matched analysis comparing outcomes in the CLEAR-ER trial to the NINDS tPA trial. [18]

Our study has few limitations which may affect generalizabilty of our findings. Firstly, lack of internal validity due to unequal distribution of relevant baseline patients' characteristics among various studies. There was also some heterogeneity in the definitions of clinical outcomes such as sICH in the included studies. Data on proportion of patients showing clinical deterioration following initial improvement after combination therapy use due to etiologies other than sICH was not provided by most of the previously published studies included in our pooled analysis. Due to limited available data in the studies included in our meta-analysis, we could not adjust our results for various clinical and demographic patients' characteristics. Secondly, there is also a risk of selection bias among the smaller case series included in our study due to lack of randomization or matching. Thirdly, none of the studies included in our analysis were powered to assess efficacy of combination therapy in comparison to standard dose tPA therapy. Lastly, due to the small number of available studies dealing with rtPA therapy in combination with a GpIIb/IIIa inhibitor and due to confounded studies, a meaningful conclusion on the benefit or harm of this combined therapy in stroke patients is not feasible.

Our study shows that the combination of low dose IV tPA with GPIIb/IIIa inhibitor is associated with reduction in sICH rates in patients with acute ischemic stroke, as compared to 0.9 g/kg IV tPA alone. There was a trend toward benefit in functional outcome at 90 days in the combination therapy arm but this difference was not statistically significant. A randomized phase III clinical trial with longer follow up period is required to establish the efficacy and safety of combination therapy, as well as to identify subgroups which might benefit the most from such therapy.

 
 » References Top

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2.
Nordt TK, Moser M, Kohler B, Ruef J, Peter K, Kubler W, et al. Augmented platelet aggregation as predictor of reocclusion after thrombolysis in acute myocardial infarction. Thromb Haemost 1998;80:881-6.  Back to cited text no. 2
    
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Harker LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis 1998;8:8-18.  Back to cited text no. 3
    
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Booth NA, Robbie LA, Croll AM, Bennett B. Lysis of platelet-rich thrombi: The role of PAI-1. Ann N Y Acad Sci 1992;667:70-80.  Back to cited text no. 4
    
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Zhang ZG, Zhang L, Tsang W, Goussev A, Powers C, Ho KL, et al. Dynamic platelet accumulation at the site of the occluded middle cerebral artery and in downstream microvessels is associated with loss of microvascular integrity after embolic middle cerebral artery occlusion. Brain Res 2001;912:181-94.  Back to cited text no. 5
    
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Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab 2001;21:1393-400.  Back to cited text no. 6
    
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Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002;59:862-7.  Back to cited text no. 7
    
8.
Rubiera M, Alvarez-Sabin J, Ribo M, Montaner J, Santamarina E, Arenillas JF, et al. Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke. Stroke 2005;36:1452-6.  Back to cited text no. 8
    
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Choudhri TF, Hoh BL, Zerwes HG, Prestigiacomo CJ, Kim SC, Connolly ES Jr, et al. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. J Clin Invest 1998;102:1301-10.  Back to cited text no. 9
    
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Ding G, Jiang Q, Zhang L, Zhang ZG, Li L, Knight RA, et al. Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor. J Cereb Blood Flow Metab 2005;25:87-97.  Back to cited text no. 10
    
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Antman EM, Giugliano RP, Gibson CM, McCabe CH, Coussement P, Kleiman NS, et al. Abciximab facilitates the rate and extent of thrombolysis: Results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators. Circulation 1999;99:2720-32.  Back to cited text no. 11
    
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Peerlinck K, De Lepeleire I, Goldberg M, Farrell D, Barrett J, H and E, et al. MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. Circulation 1993;88:1512-7.  Back to cited text no. 12
    
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Zhang L, Zhang ZG, Zhang R, Morris D, Lu M, Coller BS, et al. Adjuvant treatment with a glycoprotein IIb/IIIa receptor inhibitor increases the therapeutic window for low-dose tissue plasminogen activator administration in a rat model of embolic stroke. Circulation 2003;107:2837-43.  Back to cited text no. 13
    
14.
Pancioli AM, Broderick J, Brott T, Tomsick T, Khoury J, Bean J, et al. CLEAR Trial Investigators. The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: The CLEAR stroke trial. Stroke 2008;39:3268-76.  Back to cited text no. 14
    
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Pancioli AM, Adeoye O, Schmit PA, Khoury J, Levine SR, Tomsick TA, et al. CLEAR-ER Investigators. Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial. Stroke 2013;44:2381-7.  Back to cited text no. 15
    
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Gahn G, Barlinn K, Dzialowski I, Puetz V, Kunz A, Hentschel H, et al. Combined thrombolysis with abciximab and rtPA in patients with middle cerebral artery occlusion. Acta Neurol Scand 2010;121:63-6.  Back to cited text no. 16
    
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Morris DC, Silver B, Mitsias P, Lewandowski C, Patel S, Daley S, et al. Treatment of acute stroke with recombinant tissue plasminogen activator and abciximab. Acad Emerg Med 2003;10:1396-9.  Back to cited text no. 17
    
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Adeoye O, Knight WA, Khoury J, Schmit PA, Sucharew H, Broderick JP, et al. A matched comparison of eptifibatide plus rt-PA versus rt-PA alone in acute ischemic stroke. J Stroke Cerebrovasc Dis 2014;23:e313-5.  Back to cited text no. 18
    



 
 
    Tables

  [Table 1], [Table 2]

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