Intracranial Bleeding After Reperfusion Therapy in Acute Ischaemic Stroke Patients Randomized to Glyceryl Trinitrate vs. Control: An Individual Patient Data Meta-Analysis

Abstract

Background: Thrombolysis, with or without thrombectomy, for acute ischaemic stroke is associated with an increased risk of intracranial bleeding. We assessed whether treatment with glyceryl trinitrate (GTN), a nitric oxide donor, may influence the associated bleeding risk. Methods: We searched for completed randomized controlled trials of GTN vs. no GTN in acute ischaemic stroke with data on reperfusion treatments (thrombolysis and/or thrombectomy). The primary efficacy outcome was functional status as assessed by the modified Rankin Scale (mRS) at day 90; the primary safety outcome was intracranial bleeding. Secondary safety outcomes included symptomatic intracranial hemorrhage and haemorrhagic transformation of infarction. Individual patient data were pooled and meta-analysis performed using ordinal or binary logistic regression with adjustment for trial and prognostic variables both overall and in those randomized within 6 h of symptom onset. Results: Three trials met the eligibility criteria. Of 715 patients with ischaemic stroke who underwent thrombolysis (709, >99%) or thrombectomy (24, 3.4%), 357 (49.9%) received GTN and 358 (50.1%) received no GTN. Overall, there was no difference in the distribution of the mRS at day 90 between GTN vs. no GTN (OR 0.94, 95% CI 0.72-1.23; p = 0.65); similarly, there was no difference in intracranial hemorrhage rates between treatment groups (OR 0.90, 95% CI 0.43-1.89; p = 0.77). In those randomized to GTN vs. no GTN within 6 h of symptom onset, there were numerically fewer bleeding events, but these analyses did not reach statistical significance. Conclusions: In ischaemic stroke patients treated predominantly with thrombolysis, transdermal GTN was safe, but did not influence functional outcome at 90 days.

Keywords: bleeding; glyceryl trinitrate; ischaemic stroke; meta-analysis; reperfusion; thrombectomy; thrombolysis.

Figure 1

Acute ischaemic stroke patients who underwent reperfusion strategies. Distribution of mRS at day 90 by GTN vs. no GTN: adjusted OR 0.94, 95% CI 0.72–1.23, p = 0.65. CI, confidence interval; GTN, glyceryl trinitrate; mRS, modified Rankin Scale; OR, odds ratio.

Figure 2

Acute ischaemic stroke patients who underwent reperfusion strategies and randomized to GTN vs. no GTN within 6 h of onset. Distribution of mRS at day 90 by GTN vs. no GTN: adjusted OR 0.81, 95% CI 0.56–1.18, p = 0.27. CI, confidence interval; GTN, glyceryl trinitrate; mRS, modified Rankin Scale; OR, odds ratio.

Figure 3

Forest plot of effect on mRS at day 90 in pre-defined subgroups for acute ischaemic stroke patients who underwent reperfusion strategies by GTN vs. no GTN. Unadjusted ordinal logistic regression for mRS at day 90 with interaction between subgroup and GTN vs. no GTN. BP, blood pressure; CI, confidence interval; ENOS, Efficacy of nitric oxide in stroke trial; GTN, glyceryl trinitrate; LACS, lacunar syndrome; mRS, modified Rankin scale; NIHSS, National Institutes for Health Stroke Scale; OCSP, Oxfordshire community stroke project; OTR, onset to randomization; PACS, partial anterior circulation syndrome; POCS, posterior circulation syndrome; RIGHT, Rapid intervention with glyceryl trinitrate in hypertensive stroke trial; TACS, total anterior circulation syndrome.