CNS Neuroscience & Therapeutics: Butylphthalide combined with recanalization is safe and effective

In October 2022, the latest research results of the team of Professor Yang Qingwu and Zi Wenjie of the Second Affiliated Hospital of Army Medical University (Xinqiao Hospital).
Efficacy and safety of 3-n-butylphthalide combined with endovascular treatment in acute ischemic stroke due to large vessel occlusion" in CNS Neuroscience & Published in Therapeutics (IF=7.
035).

This study combined a database of three studies of patients with acute ischemic stroke with macrovascular occlusion and endovascular therapy to demonstrate that butylphthalide combined with endovascular therapy improves functional outcomes and reduces the risk of death without increasing the risk
of symptomatic intracranial haemorrhage in patients with acute ischemic stroke due to macrovascular occlusion.

Research background

Endovascular therapy (EVT) has made great progress in recent years as a first-line treatment for acute intracranial macrovascular occlusion (LVO).

Despite successful recanalization rates greater than 80%, many patients experience clinical deterioration after successful reperfusion and often have a poor prognosis, a phenomenon known as ineffective recanalization (FR).

ONE FROM FIVE WELL-KNOWN RANDOMIZED CONTROLLED TRIALS (EXTEND-IA, MR CLEAN, SWIFT-PRIME, ESCAPE, AND ESCAPE REVASCAT) META-ANALYSIS FOUND THAT THE INCIDENCE OF FR AFTER EVT WAS 54%.

A large number of experiments have confirmed that butylphthalide (NBP) has the effect
of protecting mitochondrial function, improving microcirculation dysfunction, reducing inflammatory response and oxidative stress.
Since the launch of butadiphthalide, several studies have shown that butadiphthalide can reduce cerebral ischemic damage and improve functional prognosis
in AIS patients without EVT.
However, the efficacy and safety of NBP in combination with EVT in patients with LVO is unclear
.
This study used a national joint database of three studies to assess whether NBP in combination with EVT could improve functional outcomes
in patients with LVO.

Research methods

This study was analyzed using data from three EVT studies on LVO leading to AIS patients, including: the BASILAR study (coverage 47 A national registry study of acute basilar artery occlusion in stroke centres), the DEVT study (a multicentre open-label randomized controlled trial covering anterior circulation LVOs in 33 stroke centres), and one study on national LVOs A multicenter study
of the safety and efficacy of endovascular therapy for AIS.
Inclusion criteria were ≥ 18 years of age and post- or anterior-circulation LVO confirmed by head digital subtraction angiography, magnetic resonance angiography (MRA), or computed tomography angiography (CTA), EVT treatment
within 24 hours of the estimated LVO time.
Exclusion criteria include premorbid mRS score of 3 or greater, allergy to butadiphthalide, intracerebral haemorrhage on presentation with CTA or MRA, or lack of data on butadiene use, Severe hepatic, kidney, or cardiopulmonary dysfunction
.

All patients received EVT, including endarterial therapy, pharmacotherapy, balloon angioplasty, stenting, or a combination of therapies
.
Early application of butylphthalide in patients after EVT is initiated at the discretion of the investigator and initiated
within 24 hours of mechanical recanalization.
If bauxinol is given early, sodium chloride injection (100 ml, 2 times a day) is used for slow intravenous infusion for at least 50 minutes, and after 14 days of treatment, oral butylphthalide softgels (100 mg * 2, 3 times a day) are administered sequentially for 90 days
.

Study results

A total of 1820 patients were included in this study, including 682 (37.
5%) patients in the butyranide group and 1138 (62.
5%) patients in the control group
.
The median age was 66 years, the baseline NIHSS score was 17, and intravenous thrombolysis (IVT) accounted for 25.
8%
of patients.
A total of 1524 (84.
1%) patients achieved complete recanalization (mTICI 2b-3).

There was no statistically significant difference in baseline characteristics between the two groups after propensity score matching (p>0.
05).

Fig.
1 Baseline data: Patients with acute macrovascular occlusive stroke

The median mRS at day 90 was 3(2-5) in the butyrophthalide group and 4(2-6) in the control group (p<0.
001
).
After a 1:1 propensity score match, the baseline characteristics of the butyrophthalide group and the control group were balanced
.
The median day-90 mRS of 3 [1–5] in the butyranide group was also significantly lower than 4 [2–6] (p<0.
001)
in the control group.
The proportions of 0-1, 0-2 and 0-3 in the 90-day mRS in the butylphthalide group were still significantly higher than those in the control group (28.
0% vs.
22.
0%, p=0.
016; 42.
2% vs.
33.
7%, p=0.
003; 55.
4% vs.
44.
7%, p<0.
001
).

Fig.
2 Distribution of mRS scores on day 90 between butylphthalide group and control group

At 90 days, 378 (55.
4%) patients in the butyranide group had a good functional prognosis (adjusted OR: 1.
589, 95% CI: 1.
251–2.
020, p<0.
001) compared with 486 (42.
7%) in the control group (adjusted OR: 1.
507, 95% CI: 1.
031–1.
658, p=0.
027) A total of 193 (28.
3%) patients in the butylphthalide group had a better functional prognosis than 244 (21.
4%) in the control group (adjusted OR: 1.
362, 95% CI: 1.
052–1.
763, p=0.
019).

。 In terms of safety, a total of 229 (12.
7%) patients developed sICH, 10.
9% in the butyranide group, 13.
8% in the control group (adjusted OR: 0.
787, p=0.
152), and the mortality rate in the butylphthalide group was 21.
7%, which was significantly lower than that in the control group of 36.
7% (adjusted OR: 0.
486, p<0.
001).

Figure 3 Safety and efficacy

In subgroup analyses, bartyrphthalide was consistent
in functional outcomes at 90 days in any prespecified subgroup (by age, sex, baseline NIHSS, baseline ASPECTS score, onset-to-recanalization time, occlusion site, mTICI, and intravenous thrombolytic stratification).
Interaction analysis also showed no heterogeneity in the efficacy of butylphthalide (interaction p>0.
05).

Figure 4 90-day mRS subgroup analysis

Conclusion of the study

This study is currently the largest registry study to explore the efficacy and safety of butylphthalide in combination with EVT in Chinese populations in patients with
LVO-induced AIS.
In AIS-LVO patients, NBP was found to be significantly associated with
reduced mortality within 90 days and improved functional outcomes.
All predetermined exploratory subgroups based on age, sex, baseline NIHSS, baseline ASPECTS score, and intravenous thrombolysis showed favorable results
for butylphthalide use.
After adjusting for baseline differences, there was no heterogeneity between basilar artery occlusion (BAO) and anterior circulation LVO in 90-day mRS scores and mortality, which further validated the results of
the study.
On the basis of vascular recanalization, butylphthalide may have a potentially neurovascular protective effect, thereby improving the 90-day functional prognosis and reducing the risk of
death in patients with BAO or anterior circulation LVO.