Former antiplatelet drug administration and consequences of intravenous thrombolysis in acute ischemic stroke

Abstract

BACKGROUND:

One of the concerns in patients with acute ischemic stroke with former history of taking antiplatelet drugs is the risk of intracerebral hemorrhage following venous thrombolysis. The purpose of this study was to evaluate the effect of previous administration of antiplatelet drugs on adverse outcomes of recombinant tissue plasminogen activator (tPA) in patients with acute ischemic stroke.

METHODS:

In this study, 46 patients with the diagnosis of acute ischemic stroke were recruited. Patients were assessed in a period of three hours after stroke and received the standard dose of tPA (0.9 mg/kg). History of antiplatelet drugs, risk factors, demographic information and stroke severity were collected. The severity of the stroke was determined by the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed using the Modified Rankin Scale (MRS) and Barthel Index (BI) in the days one, 14 and 90.

RESULTS:

Patients with history of antiplatelet drugs had an increased rate of intracranial hemorrhage [odds ratio (95% CI) $=$ 7.3 (1.3–40.5)]. Stroke severity scores were higher in patients receiving antiplatelet drugs than the other group at discharge day and day 90. In both groups, the severity of the disease decreased with time. Mortality rate was 42.1% in patients received antiplatelet drugs and 18.5% in the other group ( $P>$ 0.05).

CONCLUSION:

Based on the results of this study, patients with acute ischemic stroke and history of taking antiplatelet drugs have poor outcome following administration of standard dose of tPA.

Keywords

tPA antiplatelet drug intracerebral hemorrhage

1. Introduction

Stroke is regarded as a deliberating disorder with high global incidence and increasing incidence in low and middle income countries [1]. Recombinant tissue plasminogen activator (tPA) is the well-known management for acute ischemic stroke [2]. However, development of intracranial hemorrhage (ICH) after administration of this thrombolytic agent might lead to early worsening of patient’s conditions and negative long-term consequences [3]. Occurrence of this devastating condition has been associated with several risk factors such as advanced age, higher stroke severity, elevated glucose levels, existence of atrial fibrillation, congestive heart failure, renal failure and prior antiplatelet taking [4]. Based on the fact that a large number of stroke patients have a history long-term antiplatelet therapy, tPA should be administered with caution. In line with these observations, European Stroke Organization guideline has regarded former antiplatelet therapy as a “warning sign” of low safety of thrombolysis [5]. A standard protocol has been established for treatment of appropriate stroke patients tPA in Iran based on the regional limitations [6]. Although several risk factors have been regarded as contraindications for tPA [7], there is no consensus about administration of tPA in patients with former antiplatelet therapy. In the present study, we assessed occurrence of ICH in 46 stroke patients who received tPA in association with history of antiplatelet drugs.

2. Methods

The current observational cohort study was conducted in stroke patients referred to Sina Farshchian Hospital, Hamadan, Iran during 2016–2017. Patients were assessed in a period of three hours after stroke and received the standard dose of tPA (0.9 mg/kg). Demographic data, history of antiplatelet drugs, risk factors (hypertension, hyperlipidemia, diabetes, smoking, previous myocardial infarction or former stroke) and stroke severity were collected. The severity of the stroke was determined by the National Institutes of Health Stroke Scale (NIHSS). The outcome was assessed using the Modified Rankin Scale (MRS) and Barthel Index (BI) in the days one, 14 and 90. The risk of symptomatic intracerebral hemorrhage (sICH) was also assessed in all patients.

Patients were divided in two groups based on history of antiplatelet treatments. Data were analyzed using SPSS version 16 (IBM Corp, Armonk, NY). Quantitative and qualitative variables were compared between two groups using Mann-Whitney U and Chi square tests respectively.

3. Results

A total of 46 ischemic stroke patients (male/female ratio: 21 (54.4%)/25 (45.6%), mean age $\pm$ standard deviation (SD): 71 $\pm$ 11.91) entered the study. Nineteen patients (41.3%) have history of long-term antiplatelet therapy. There was no significant difference between age of patients with/without history of antiplatelet therapy (73.68 $\pm$ 2.72 versus 69.11 $\pm$ 2.26). Other baseline characteristics were also not different between two groups. Table 1 shows the demographic and clinical data of patients.

Although the mortality within the 3 month follow-up period was not significantly different between two groups ( $P$ value $=$ 0.08), the occurrence of sICH was significantly higher in patients with history of antiplatelet therapy compared with the other group ( $P=$ 0.01). Table 2 shows the frequency of mortality, sICH and abnormal CT scan results in two study groups.

Table 3
Comparison of stroke severity in study groups in the days one, discharge day and day 90 based on National Institute of Health Stroke Scale (NIHSS), Modified Rankin Scale (MRS) and Barthel Index (BI) (N1: number of patients in day 1 and discharge day, N2: Number of patients in day 90)

	Positive antiplatelet therapy	Negative antiplatelet therapy	$P$ value
	(N1 $=$ 19, N2 $=$ 11)	(N1 $=$ 27, N2 $=$ 22)	(Mann-Whitney test)
NIHSS
Day1	16.15 $\pm$ 1.48	12.44 $\pm$ 1.41	0.06
Discharge day	20.31 $\pm$ 3.09	12.77 $\pm$ 2.92	0.01
Day 90	8.36 $\pm$ 1.91	3.95 $\pm$ 1.23	0.01
MRS
Day1	4.52 $\pm$ 0.14	3.66 $\pm$ 0.22	0.01
Discharge day	4.52 $\pm$ 0.31	3.07 $\pm$ 0.35	0.01
Day 90	2.90 $\pm$ 0.34	1.54 $\pm$ 0.33	0.01
BI
Day1	38.14 $\pm$ 6.31	19.21 $\pm$ 4.34	0.06
Discharge day	51.11 $\pm$ 6.96	26.57 $\pm$ 6.17	0.02
Day 90	59.54 $\pm$ 8.61	79.09 $\pm$ 5.70	0.05

Based on the NIHSS, no significant difference was found in stroke severity between two groups at day 1. However, stroke severity score was higher in patients with history of antiplatelet therapy compared with the other group in discharge day and day 90 ( $P$ values $=$ 0.01). BI score was higher in patients with history of antiplatelet therapy compared with the other group in only discharge day ( $P=$ 0.02). Based on MRS, stroke severity score was higher in patients with history of antiplatelet therapy compared with the other group in all three times ( $P=$ 0.01). Table 3 shows stroke severity scores in three time intervals.

Administration of tPA in ischemic stroke patients was associated with 7.29 times higher risk of sICH in patients with history of antiplatelet therapy compared with the other group (Odds ratio (95% Confidence Intervals) $=$ 7.29 (1.31–40.54), $P$ value $=$ 0.02).

We classified patients to good/bad prognosis based on the MRS level ( $<$ 2 versus $>$ 2). No significant difference was found between two groups at day 1. However, patients with history of antiplatelet therapy had worse prognosis on discharge day and day 90 compared with other group.

4. Discussion

Although intravenous tPA is administered to ameliorate outcomes in ischemic stroke, patients with prior antiplatelet therapy might experience a greater risk of bleeding after tPA administration. In the current study, we compared occurrence of sICH and stroke severity following tPA administration in patients with and without history of antiplatelet therapy. We found higher prevalence of sICH in patients received antiplatelet treatment. In addition, based on NIHSS stroke severity score was higher in patients with history of antiplatelet therapy compared with the other group in discharge day and day 90 in spite of similar scores in day 1. A previous observational study in a large cohort of stroke patients who took tPA has shown a higher risk for sICH but better functional outcomes in patients who received pre-stroke antiplatelet therapy [8]. Our results are in accordance with them in terms of higher sICH prevalence but not in patients’ outcome. Although there were no significant differences in age, time from stroke to referral to hospital and time from hospitalization to tPA administration between two groups in our study, we cannot rule out higher prevalence of other comorbidities in the patients who had history of antiplatelet therapy. So the poor outcome in this group might be due to presence of other disorders such as cardiovascular disorders.

Based on the results of this study, patients with acute ischemic stroke and history of taking antiplatelet drugs have poor outcome following administration of standard dose of tPA. However, future studies are needed to explore the effects of lower doses of tPA in these patients. A previous in Asian patients with acute ischemic stroke showed lesser occurrence of sICH after administration of low-dose tPA. However, it did not show the non-inferiority of low-dose tPA to standard-dose tPA in terms of mortality and morbidity at 90 days [9].

5. Conclusion

Although the sample size of our study was low, our study was the first study in Iranian population. Administration of tPA has several limitations in Iran among them are prehospital deferment, financial limitations due to lack of insurance coverage and nonexistence of infrastructure [10]. On the other hand, clinical response to tPA has been associated with a number genetic polymorphisms [11], which necessitate population-based studies to unravel pattern of clinical responses and adverse effects based on ethnicity of patients. In brief, our results warrants further studies in larger sample sizes to assess clinical significance of tPA in Iranian patients.

Footnotes

Acknowledgments

The current study was supported by a grant from Hamadan University of Medical Sciences.

Conflict of interest

The authors declare they have no conflict of interest.

Abbreviations

Table 1

Demographic and clinical data of patients

	Positive antiplatelet therapy	Negative antiplatelet therapy	$P$ value
Age (mean $\pm$ SD, year)	73.68 $\pm$ 2.72	69.11 $\pm$ 2.26	0.13
Time from stroke to referral to hospital (mean $\pm$ SD, minute)	96.78 $\pm$ 9.80	92.62 $\pm$ 8.86	0.82
Time from hospitalization to tPA administration	59.73 $\pm$ 5.77	66 $\pm$ 7.56	0.97
(mean $\pm$ SD, minute)

Table 2

The frequency of mortality, sICH and abnormal CT scan results in two study groups

	Positive antiplatelet therapy	Negative antiplatelet therapy	$P$ value (fisher exact test)
Mortality	8 (42.1%)	5 (18.5%)	0.08
sICH	7 (36.8%)	2 (7.4%)	0.01
Abnormal initial brain CT scan	2 (10.5%)	1 (3.7%)	0.56
Abnormal second brain CT scan	13 (68.4%)	11 (40.7%)	0.08

References

Feigin

V.L.

Lawes

C.M.

Bennett

D.A.

Barker-Collo

S.L.

and Parag

, Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review, The Lancet. Neurology 8 (2009), 355–369.

Demaerschalk

B.M.

et al., Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association, Stroke 47 (2016), 581–641.

TNIoNDa

, Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA stroke study group, The New England Journal of Medicine 333 (1995), 1581–1587.

Whiteley

W.N.

Slot

K.B.

Fernandes

Sandercock

and Wardlaw

, Risk factors for intracranial hemorrhage in acute ischemic stroke patients treated with recombinant tissue plasminogen activator: a systematic review and meta-analysis of 55 studies, Stroke 43 (2012), 2904–2909.

Ringleb

P.A.

, Guidelines for management of ischaemic stroke and transient ischaemic attack 2008, Cerebrovascular diseases (Basel, Switzerland) 25 (2008), 457–507.

Ghandehari

, Design of a standard Iranian protocol of Intravenous thrombolysis with tissue plasminogen activator: a national project, Iranian Journal of Neurology 12 (2013), 72–74.

Roth

J.M.

, Recombinant tissue plasminogen activator for the treatment of acute ischemic stroke, Proceedings 24 (2011), 257–259.

Xian

et al., Risks and benefits associated with prestroke antiplatelet therapy among patients with acute ischemic stroke treated with intravenous tissue plasminogen activator, JAMA Neurology 73 (2016), 50–59.

Anderson

C.S.

et al., Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke, N Engl J Med 374 (2016), 2313–2323.

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