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Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial

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Year of Publication: 2024

Authors: Wenbo Zhao, MD; Sijie Li, MD; Chuanhui Li, ..., MD; Xunming Ji

Journal: JAMA Neurology

Citation: JAMA Neurol. 2024;81(6):594-602. doi:10.1001/jamaneurol.2024.0868

Link: https://doi.org/10.1001/jamaneurol.2024.0868

Clinical Question

To determine whether intravenous tirofiban administered within 24 hours of stroke onset prevents early neurological deterioration in patients with acute noncardioembolic stroke compared with oral aspirin.

Bottom Line

In Chinese patients with acute noncardioembolic ischemic stroke presenting within 24 h and NIHSS 4-20, 72-hour intravenous tirofiban significantly reduced early neurological deterioration within 72 h compared with oral aspirin (4.2% vs 13.2%; aRR 0.32) without increasing symptomatic ICH (0% in both groups) or systemic bleeding. The benefit did NOT translate into statistically significant improvements in 90-day mRS outcomes.

Major Points

  • 426 patients were randomized (214 tirofiban, 212 aspirin) at 10 Chinese centers; 425 were included in the modified intention-to-treat analysis (213 tirofiban, 212 aspirin; 1 tirofiban patient lost to follow-up within 72 h).
  • Primary outcome (early neurological deterioration, defined as NIHSS increase ≥4 within 72 h) occurred in 4.2% (9/213) of tirofiban patients vs 13.2% (28/212) of aspirin patients (adjusted RR 0.32; 95% CI 0.16-0.65; P=.002).
  • No patients in either group experienced symptomatic intracerebral hemorrhage.
  • Excellent 90-day functional outcome (mRS 0-1) was 75% (159/212) with tirofiban vs 68.4% (145/212) with aspirin (adjusted RR 1.08; 95% CI 0.97-1.21; P=.16) — NOT statistically significant.
  • 90-day mRS shift analysis: median 1 (IQR 0-1.25) tirofiban vs 1 (IQR 0-2) aspirin; adjusted common OR 1.28 (95% CI 0.90-1.83; P=.17).
  • 90-day mortality: 3/226 (1.3%) tirofiban vs 3/198 (1.5%) aspirin (adjusted RR 1.15; 95% CI 0.27-8.54; P=.63); serious adverse events and bleeding events did not differ significantly.

Design

Study Type: Investigator-initiated, multicenter, prospective, open-label, randomized clinical trial with blinded end-point assessment (PROBE design)

Randomization: 1

Blinding: Open-label treatment; outcome assessors and trial steering committee blinded to allocation (PROBE).

Enrollment Period: September 12, 2020 to March 31, 2023

Follow-up Duration: 90 days

Centers: 10

Countries: China

Sample Size: 425

Analysis: Modified intention-to-treat (mITT) for primary and secondary efficacy analyses. Primary analysis used Poisson regression with robust error, adjusted for age, sex, location of infarction, baseline NIHSS score, prestroke antiplatelet therapy, and etiological stroke subtype (TOAST). Relative risk with 95% CI. mRS shift analyzed using proportional odds model. Sensitivity analyses on full analysis set (FAS) and per-protocol population. Safety analyses on safety set (patients who received tirofiban within 72 h). No interim analyses; no multiplicity adjustment for secondary outcomes. R version 4.3.1.

Inclusion Criteria

  • Adults aged 18 to 80 years
  • Acute ischemic stroke within 24 hours of symptom onset or time last known well
  • NIHSS score of 4 to 20 at randomization
  • Medical Research Council motor score ≥2 for paralyzed limbs (to alleviate NIHSS ceiling effect)
  • Noncardioembolic stroke etiology

Exclusion Criteria

  • NIHSS score <4 or >20
  • MRC motor score of 0 or 1 for paralyzed limbs
  • Cardioembolic stroke (suspected or confirmed)
  • Prestroke mRS ≥2
  • Received intravenous thrombolysis or endovascular thrombectomy
  • Time from stroke onset >24 h
  • Transient ischemic attack
  • Hematochezia or active bleeding
  • Severe kidney failure
  • Contraindication to antiplatelet therapy or tirofiban
  • Did not provide informed consent

Baseline Characteristics

CharacteristicControlActive
Age, y, median (IQR)64 (56-71)64 (56-70)
Male, n (%)147 (69.3)154 (72.3)
Female, n (%)65 (30.7)59 (27.7)
History of hypertension, n (%)134 (63.2)132 (62.0)
History of diabetes, n (%)67 (31.6)68 (31.9)
History of dyslipidemia, n (%)25 (11.8)24 (11.3)
History of coronary heart disease, n (%)28 (13.2)27 (12.7)
History of cerebral infarction, n (%)59 (27.8)57 (26.7)
History of intracerebral hemorrhage, n (%)7 (3.3)5 (2.3)
Previous smoking, n (%)103 (48.6)97 (45.5)
Current smoking, n (%)87 (41.0)82 (38.5)
Prior single antiplatelet, n (%)65 (30.7)62 (29.1)
Prior dual antiplatelet, n (%)6 (2.8)10 (4.7)
Baseline NIHSS score, median (IQR)5 (4-8)5 (4-7)
NIHSS <10, n (%)176 (83.0)188 (88.3)
NIHSS ≥10, n (%)36 (17.0)25 (11.7)
Anterior circulation infarct, n (%)112 (52.8)126 (59.2)
Posterior circulation infarct, n (%)53 (25.0)47 (22.1)
Anterior and posterior circulation, n (%)17 (8.0)8 (3.8)
Undefined infarct location, n (%)30 (14.2)32 (15.0)
Systolic BP at randomization, mm Hg, median (IQR)153 (138.5-168)155 (140-168)
Diastolic BP at randomization, mm Hg, median (IQR)88 (78.5-99)88 (79-97)
Glucose at admission, mmol/L, median (IQR)6.4 (5.4-9.0)6.4 (5.4-9.2)
Stroke cause — large-artery atherosclerosis, n (%)65 (30.7)49 (23.0)
Stroke cause — cardioembolism, n (%)5 (2.4)4 (1.9)
Stroke cause — small-vessel occlusion, n (%)52 (24.5)72 (33.8)
Stroke cause — other determined, n (%)3 (1.4)0 (0)
Stroke cause — undetermined, n (%)87 (41.0)88 (41.3)
Time from onset to randomization, h, median (IQR)10.5 (6.6-21.0)12.5 (7.8-19.2)
≤12 h from onset, n (%)126 (59.4)114 (53.5)
>12 h from onset, n (%)86 (40.6)99 (46.5)

Arms

FieldTirofiban GroupControl
InterventionIntravenous tirofiban (tirofiban hydrochloride and sodium chloride injection): 0.4 μg/kg/min for 30 minutes, followed by continuous infusion of 0.1 μg/kg/min for up to 71.5 hours (72 h total). Subsequently transitioned to oral aspirin with a 4-hour overlap. All patients received aspirin 150-300 mg/d during first 2 weeks then 100-300 mg/d for secondary prevention.Oral aspirin (Bayer) 150-300 mg/d during the first 2 weeks after symptom onset, then 100-300 mg/d thereafter for secondary prevention (open-label; no placebo infusion).
Duration72-hour infusion followed by oral aspirin through 90-day follow-up90 days

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Early neurological deterioration (END) within 72 hours of randomization, defined as an increase in NIHSS score of ≥4 points at any time within 72 hours compared with the score immediately before randomization (modified intention-to-treat population).Primary13.2% (28/212 patients)4.2% (9/213 patients)0.320.002
Early neurological deterioration — alternate definition (NIHSS increase ≥2 within 72 h)Secondary23.6% (50/212 patients)11.7% (25/213 patients)0.490.001
Excellent functional outcome (mRS 0-1) at 90 daysSecondary68.4% (145/212 patients)75.0% (159/212 patients)1.080.16
Functional independence (mRS 0-2) at 90 daysSecondary85.8% (182/212 patients)89.2% (189/212 patients)1.030.47
mRS 0-3 at 90 daysSecondary92.9% (197/212 patients)93.9% (199/212 patients)10.88
Shift on mRS at 90 days (ordinal analysis)SecondaryMedian 1 (IQR 0-2)Median 1 (IQR 0-1.25)0.17
Early improvement (NIHSS decrease ≥4 within 72 h)Secondary13.2% (28/212 patients)13.1% (28/213 patients)1.130.62
Symptomatic intracerebral hemorrhage (sICH) within 72 hAdverse0% (0/198 patients)0% (0/226 patients)
Any intracerebral hemorrhage within 72 hAdverse1.0% (2/198 patients)0% (0/226 patients)
Death from any cause within 90 daysAdverse1.5% (3/198 patients)1.3% (3/226 patients)1.150.63
Serious adverse events within 90 daysAdverse2.0% (4/198 patients)2.2% (5/226 patients)1.310.69

Criticisms

  • Open-label design (only outcome assessors blinded); patients and treating physicians aware of assignment.
  • Conducted exclusively in Chinese patients at 10 centers, limiting generalizability to other populations (high proportion of intracranial atherosclerosis in Chinese stroke patients).
  • Excluded severe stroke (NIHSS >20), minor stroke (NIHSS <4), cardioembolic stroke, and patients receiving IV thrombolysis or endovascular thrombectomy — limits generalizability.
  • Follow-up imaging was not mandatory, which may lead to underreporting of asymptomatic ICH.
  • Mechanisms of neurological deterioration (stroke progression, recurrent stroke, other) were not distinguished.
  • Benefit on early ND did not translate into a statistically significant improvement in 90-day mRS outcomes or in NIHSS score change at 24 h or 72 h.
  • Article was corrected on July 1, 2024 to fix errors in Table 1 and Figure 2.

Subgroup Analysis

Prespecified subgroup analyses for the primary outcome by age (≤60 vs >60 y), sex, prior antiplatelet therapy (none/single/dual), occlusion location (anterior, posterior, anterior and posterior, no infarction detected, no MRI), baseline NIHSS score (<10 vs ≥10), time from onset to randomization (≤12 vs >12 h), and TOAST stroke subtype. Point estimates favored tirofiban across all subgroups; effect appeared larger in patients >60 y, females, those without prior antiplatelet therapy, anterior circulation strokes, NIHSS <10, and large-artery atherosclerosis subtype. No formal treatment-by-subgroup interaction reported as significant.

Funding

Beijing Natural Science Foundation (JQ22020), National Key R&D Program of China (2022YFC2408800 and 2016YFC1301502), Chinese National Ministry of Science and Technology, and Beijing Municipal Science & Technology Commission (Z201100006820143).

Based on: TREND (JAMA Neurology, 2024)

Authors: Wenbo Zhao, MD; Sijie Li, MD; Chuanhui Li, ..., MD; Xunming Ji

Citation: JAMA Neurol. 2024;81(6):594-602. doi:10.1001/jamaneurol.2024.0868

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