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NICARDIPINE Implant

Localized Nicardipine Release Implants for Prevention of Vasospasm After Aneurysmal Subarachnoid Hemorrhage

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Year of Publication: 2024

Authors: Wessels L, Wolf S, Adage T, ..., Hecht N

Journal: JAMA Neurology

Citation: JAMA Neurol. 2024;81(10):1060-1065

Link: https://doi.org/10.1001/jamaneurol.2024.2564

PDF: https://jamanetwork.com/journals/jamaneu...47946.01938.pdf

Clinical Question

Does implantation of nicardipine slow-release rods during aneurysm clipping reduce angiographic vasospasm after aSAH?

Bottom Line

Intraoperative nicardipine release implants (10 implants, 4mg each) placed around basal cerebral vasculature during aneurysm clipping significantly reduced moderate-to-severe angiographic vasospasm from 58% to 20% (P=0.02) in WFNS grade 3-4 aSAH patients. Rescue therapy need reduced from 58% to 10% (P=0.002). Safety profile equivalent to standard care. Phase 2b trial, 41 patients, 6 centers in Germany/Austria.

        Major Points
        Moderate-severe aVS reduced from 58% to 20% (P=0.02) — 38 percentage-point ARR.
Rescue therapy (IA vasodilator/PTA/induced HTN): 58% vs 10% (P=0.002).
Localized delivery: plasma nicardipine stayed below systemic active levels (max 1.27 ng/mL).
New cerebral infarcts (DCI): 32% vs 10% (P=0.13, NS — underpowered).
ICU stay trended shorter: 20.8 vs 30.2 days (P=0.06).
52-week favorable outcome: 84% vs 67% (P=0.27, NS — underpowered).
Phase 2b, 41 patients, 6 academic centers (Germany/Austria). Single-masked.
Only WFNS grade 3-4 with anterior circulation aneurysms requiring clipping.
Funded by BIT Pharma (NicaPlant manufacturer). Phase 3 needed.
Aneurysm location significantly imbalanced (P=0.01) — key confounder.

      

Design

Study Type: Phase 2b randomized clinical trial

Randomization: 1

Blinding: Single-masked (surgeon unblinded, other clinical staff masked)

Enrollment Period: April 5, 2020 to January 23, 2023

Follow-up Duration: 52 weeks

Centers: 6

Countries: Germany, Austria

Sample Size: 41

Analysis: Fisher exact test, ordinal logistic regression, ANOVA, Wilcoxon rank-sum

Inclusion Criteria

Adults with WFNS grade 3 or 4 aSAH
Ruptured anterior circulation aneurysm
Planned microsurgical aneurysm clipping
Randomization within 48 hours of rupture

Exclusion Criteria

Patients not undergoing microsurgical clipping
Non-anterior circulation aneurysm
Lack of informed consent

Baseline Characteristics

Characteristic	Control	Active
Age (mean)	54.9 (9.1)	53.6 (11.9)
Female (%)	85	67
White (%)	95	90
Smoking (%)	55	38
Hypertension (%)	20	52
Aneurysm Location	ICA (45%), ACA (35%), MCA (10%), Other (10%)	ACA (48%), MCA (43%), ICA (10%)
WFNS Grade 4 (%)	70	48

Arms

Field	Control	Nicardipine Implant
Intervention	Standard microsurgical clipping + standard of care	Microsurgical clipping + 10 nicardipine implants (4 mg each)
Duration	Single procedure	Single procedure

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Incidence of moderate-to-severe angiographic vasospasm (days 7–9)	Primary	58% (11/19)	20% (4/20)	37.89%	0.02
Need for vasospasm rescue therapy	Secondary	58%	10%		0.002
New infarcts (days 13–15)	Secondary	32%	10%		0.13
Favorable outcome at 52 weeks	Secondary	67%	84%		0.27
Serious AEs (Control)	Adverse		10 events in 9 patients (45%)
Serious AEs (Implant)	Adverse		6 events in 4 patients (19%)

Criticisms

Small sample size and phase 2b design limits generalizability
Trial limited to patients undergoing surgical clipping (not endovascular group)
Low ethnic diversity
Not powered to detect mortality or long-term functional outcome differences

Funding

BIT Pharma GmbH

Based on: NICARDIPINE Implant (JAMA Neurology, 2024)