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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 (added to standard of care) significantly reduced moderate-to-severe angiographic vasospasm from 58% to 20% (P=0.02; adjusted OR 4.98, 95% CI 1.40-17.65) 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; adjusted OR 4.98, 95% CI 1.40-17.65, P=0.01) — 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 (maximal median 1.27 ng/mL, 95% CI 1.01-1.91 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

Not explicitly listed in the published paper; CONSORT diagram reports 3 of 44 assessed patients excluded before randomization (2 did not meet inclusion criteria, 1 excluded for other reason)

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
Modified Fisher 3-4 (%)	95	85

Arms

Field	Control	Nicardipine Implant
Intervention	Microsurgical aneurysm clipping + standard of care alone	Microsurgical aneurysm clipping + 10 nicardipine implants (4 mg each) placed around basal cerebral vasculature + standard of care
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) by digital subtraction angiography	Primary	58% (11/19)	20% (4/20)	4.98 (95% CI, 1.40-17.65)	0.02 (Fisher); 0.01 (ordinal logistic regression)
Need for vasospasm rescue therapy (IA vasodilator, PTA, or induced hypertension)	Secondary	58% (11/19)	10% (2/20)		0.002
New cerebral infarcts (days 13–15)	Secondary	32% (6/19)	10% (2/20)		0.13
Favorable outcome at 52 weeks	Secondary	67% (12/18)	84% (16/19)		0.27
Mean ICU length of stay (days)	Secondary	30.2 (95% CI, 22.9-37.4)	20.8 (95% CI, 13.9-27.6)		0.06
Mean hospitalization duration (days)	Secondary	45.0 (95% CI, 27.3-62.7)	29.3 (95% CI, 12.5-46.0)		0.20
Maximal median plasma nicardipine concentration through day 21 (implant group)	Secondary	N/A	1.27 ng/mL (95% CI, 1.01-1.91)
Serious Adverse Events (through week 52)	Adverse	10 events in 9 of 20 patients (45%)	6 events in 4 of 21 patients (19%)
Treatment-emergent Adverse Events (through day 21)	Adverse	96 events	84 events		No difference between groups (per paper)

Criticisms

Small sample size and phase 2b design limits generalizability
Trial limited to patients undergoing surgical clipping (not endovascular group)
Low ethnic diversity (93% White)
Not powered to detect mortality or long-term functional outcome differences
Baseline aneurysm location significantly imbalanced between arms (P=0.01) — potential confounder

Funding

BIT Pharma GmbH

Based on: NICARDIPINE Implant (JAMA Neurology, 2024)

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

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

Content summarized and formatted by NeuroTrials.ai.

NICARDIPINE Implant

(2024)

Objective

To evaluate the safety and efficacy of localized nicardipine release implants for the prevention of moderate to severe angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH).

Study Summary

• Nicardipine implants significantly reduced moderate to severe vasospasm and need for rescue therapies compared to standard of care alone, without increasing adverse events.

Intervention

Intraoperative placement of 10 nicardipine implants (4 mg each) around the basal cerebral vasculature during microsurgical clipping of ruptured anterior circulation aneurysms, in addition to standard of care.

Inclusion Criteria

Patients with World Federation of Neurological Surgeons (WFNS) grade 3 or 4 aneurysmal subarachnoid hemorrhage from ruptured anterior circulation aneurysms requiring microsurgical clipping, enrolled within 48 hours of rupture.

Study Design

Arms: Nicardipine implant group (implants + standard care) vs. control group (standard care only).

Patients per Arm: Implant group: 21, Control group: 20

Outcome

• Primary: Moderate to severe vasospasm occurred in 20% of implant group vs. 58% in control (P = .02); • Need for rescue therapy: 10% in implant vs. 58% in control (P = .002); • New infarcts by day 15: 10% in implant vs. 32% in control (P = .13); • Favorable outcome at 52 weeks: 84% in implant vs. 67% in control (P = .27); • Serious adverse events: 19% in implant vs. 45% in control; • No difference in adverse event rate or systemic nicardipine absorption.

Bottom Line

Major Points

Moderate-severe aVS reduced from 58% to 20% (P=0.02; adjusted OR 4.98, 95% CI 1.40-17.65, P=0.01) — 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 (maximal median 1.27 ng/mL, 95% CI 1.01-1.91 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.

Study Design

Study Type: Phase 2b randomized clinical trial
Randomization: Yes
Blinding: Single-masked (surgeon unblinded, other clinical staff masked)
Sample Size: 41
Follow-up: 52 weeks
Centers: 6
Countries: Germany, Austria

Primary Outcome

Definition: Incidence of moderate-to-severe angiographic vasospasm (days 7–9) by digital subtraction angiography

Control	Intervention	HR/OR	P-value
58% (11/19)	20% (4/20)	4.98 (95% CI, 1.40-17.65) (Control incidence: 34%-80%; Intervention incidence: 6%-44%)	0.02 (Fisher); 0.01 (ordinal logistic regression)

Limitations & Criticisms

Small sample size and phase 2b design limits generalizability
Trial limited to patients undergoing surgical clipping (not endovascular group)
Low ethnic diversity (93% White)
Not powered to detect mortality or long-term functional outcome differences
Baseline aneurysm location significantly imbalanced between arms (P=0.01) — potential confounder

Citation

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

View Original Publication →

NICARDIPINE Implant

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Criticisms

Funding

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