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ARUBA

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial

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Year of Publication: 2014

Authors: Mohr JP, Parides MK, Stapf C, et al; international ARUBA investigators

Journal: Lancet

Citation: Lancet 2014;383(9917):614–621. DOI: 10.1016/S0140-6736(13)62302-8

Link: https://doi.org/10.1016/S0140-6736(13)62302-8

PDF: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119885/

Clinical Question

In adults with an unruptured brain AVM, does preventive interventional eradication reduce death or symptomatic stroke compared with medical management alone?

Bottom Line

In adults with an unruptured brain AVM, medical management alone was superior to medical management with interventional therapy for preventing the composite of death or symptomatic stroke over ~33 months (10.1% vs 30.7%; HR 0.27, 95% CI 0.14–0.54, p<0.0001), and it also reduced death or mRS ≥2. The trial was halted early for benefit of medical management; upfront intervention roughly tripled the near-term risk of stroke or death.

        Major Points
        First RCT to compare medical management alone vs interventional therapy (surgery, embolisation, and/or radiotherapy) for adults with unruptured brain AVMs; 226 randomised at 39 sites in 9 countries.
Halted early at the second planned interim analysis on April 15, 2013 by the NINDS/NIH-appointed DSMB — log-rank statistic 4.10 exceeded the prespecified stopping boundary of 2.87.
Primary composite (death or symptomatic stroke): 11/109 (10.1%) medical vs 35/114 (30.7%) interventional; HR 0.27 (95% CI 0.14–0.54), p<0.0001; as-treated HR 0.19 (0.09–0.38), p<0.0001.
Death or mRS ≥2 at 30 months: 15.1% (8/53) medical vs 46.2% (24/52) interventional (RR 0.33, 95% CI 0.16–0.66); at 36 months: 14.0% vs 38.6% (RR 0.36, 95% CI 0.16–0.83).
Neurological adverse events: total strokes 45 (interventional) vs 12 (medical), p<0.0001; non-stroke neurological deficits 14 vs 1, p=0.0008.
Spontaneous AVM rupture rate in the medical arm was low: 2.2% per year (95% CI 0.9–4.5), consistent with modern population-based cohorts.
Interventional composition: neurosurgery alone n=5, embolisation alone n=30, radiotherapy alone n=31, embolisation+neurosurgery n=12, embolisation+radiotherapy n=15, all three n=1; median time to first intervention 76 days (IQR 45–119); 20 patients had not initiated therapy at analysis.
ARUBA enrolled a favourable interventional cohort (62% Spetzler-Martin grade ≤2, none >4; 138/223 AVMs <30 mm; all baseline mRS ≤1), yet intervention still worsened outcomes.
Limitations: non-blinded, mean follow-up only 33 months, early stopping may inflate effect estimate, and many interventional patients were still awaiting or undergoing treatment at analysis.

      

Design

Study Type: Prospective, multicentre, parallel-design, non-blinded, randomised controlled superiority trial (with a non-inferiority secondary aim)

Randomization: 1

Blinding: Non-blinded (open-label) for patients, treating clinicians, and site investigators. A senior study neurologist not involved in interventional procedures performed the clinical outcome assessment; all primary and secondary events and imaging were reviewed by an independent multidisciplinary international adjudication committee.

Enrollment Period: April 4, 2007 – April 15, 2013 (halted early)

Follow-up Duration: Mean 33.3 months (SD 19.7; median 33.2, IQR 16.3–49.8) at primary analysis; observational phase planned to continue for an additional 5 years

Centers: 39

Countries: 9 countries (site list not enumerated in the primary manuscript)

Sample Size: 226

Power Calculation: Original design: 800 patients, assumed 5-year event rates of 22% interventional vs 12% medical, giving 87.5% power to detect a 40% hazard reduction. Revised (after slow accrual) to 400 patients, providing 80% power to detect a 46% hazard reduction. Actual accrual at halt: 226 (~53% of anticipated outcome information).

Analysis: Intention-to-treat (as-randomised) primary analysis using a 0.05-level log-rank test; Kaplan-Meier stroke-free survival curves; Cox proportional-hazards regression for HRs, with prespecified interaction tests for Spetzler-Martin grade, AVM location, venous drainage pattern, age, and time from AVM discovery. As-treated sensitivity analysis (crossovers analysed by management actually received). Two prespecified interim analyses used a Lan-DeMets stopping boundary with an O'Brien-Fleming spending function. mRS ≥2 outcomes compared by χ² test; adverse-event rates compared by Poisson regression.

Inclusion Criteria

Age ≥18 years
Unruptured brain arteriovenous malformation diagnosed by appropriate neurovascular imaging (catheter angiography, MRI/MR angiography, or CT/CT angiography)
AVM deemed suitable for attempted eradication by the local ARUBA centre
Modified Rankin Scale score ≤1 at baseline
Written informed consent

Exclusion Criteria

Any imaging evidence of previous haemorrhage from the brain AVM
Any previous interventional treatment attempt for the AVM
AVM deemed unsuitable for attempted eradication by the local centre

Baseline Characteristics

Characteristic	Interventional therapy (n=114)	Medical management (n=109)
Mean age (years)	44.5 (SD 12.3, overall range 20–69)	44.5 (SD 12.3, overall range 20–69)
Women (%)	~41% (overall cohort)	~41% (overall cohort)
White (%)	~83% (overall cohort)	~83% (overall cohort)
African American (%)	~7% (overall cohort)	~7% (overall cohort)
Hispanic ethnicity (%)	~12% (overall cohort)	~12% (overall cohort)
AVM <30 mm (n across whole cohort)	138	138
AVM 30–60 mm (n across whole cohort)	85	85
Spetzler-Martin grade ≤2 (%)	~62% (none >4)	~62% (none >4)
Baseline mRS ≤1	100% (by entry criterion)	100% (by entry criterion)
Baseline neurological symptoms	Slightly more common than in medical arm (minor imbalance noted by authors)

Arms

Field	Interventional therapy + medical management	Control
Intervention	Any neurosurgical, endovascular embolisation, and/or stereotactic radiotherapy procedure(s), alone or combined, chosen by local investigators to achieve complete AVM eradication, plus pharmacological therapy for symptoms and vascular risk factors as needed	Pharmacological therapy for existing symptoms (seizures, headaches) and coexisting vascular risk factors (hypertension, diabetes) as needed, without planned AVM eradication
N	114	109

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to composite of death from any cause or symptomatic stroke (haemorrhage on CT/MRI/CSF, or new ischaemic lesion on CT or DWI/T2/FLAIR MRI, with any new focal deficit, seizure, or new-onset headache)	Primary	11/109 (10.1%)	35/114 (30.7%)	0.27	<0.0001
Death or mRS ≥2 at 30 months (as-randomised)	Secondary	8/53 (15.1%)	24/52 (46.2%)	0.33	significant (exact p not stated)
Death or mRS ≥2 at 36 months (as-randomised)	Secondary	6/43 (14.0%)	17/44 (38.6%)	0.36	significant (exact p not stated)
Spontaneous AVM rupture rate in medical arm	Secondary	2.2% per year (95% CI 0.9–4.5)	n/a		n/a
Total strokes (including recurrent post-primary events)	Safety	12	45		<0.0001
Non-stroke neurological deficits	Safety	1	14		0.0008
Discontinuation of trial participation during follow-up	Safety	2/109 (~2%)	5/114 (~4%)

Subgroup Analysis

Prespecified interactions tested for Spetzler-Martin grade, AVM location, venous drainage pattern, age, and time from AVM discovery. Primary event rates in the medical arm were low across all Spetzler-Martin grades, whereas interventional-arm events were significantly more frequent in Spetzler-Martin grades II–III in both as-randomised and as-treated analyses. Primary event incidence did not differ across participating countries.

Criticisms

Non-blinded (open-label) design — although outcome events were objective and centrally adjudicated.
Early stopping at the second interim (only 53% of planned outcome information) may inflate the effect estimate for medical management.
Short follow-up (~33 months) relative to a lifelong disease; any delayed benefit of eradication (e.g., after successful radiosurgery latency) could accrue only later.
20/116 interventional patients had not initiated therapy and 53 had ongoing treatment plans at analysis — because procedural harm clusters near treatment, the near-term comparison may not reflect steady-state outcomes.
Small final sample (226 vs original 800 target) — underpowered to compare interventional modalities (surgery vs embolisation vs radiotherapy) or to detect modality-specific safety.
Enrolled a highly selected 'optimum' interventional cohort (62% Spetzler-Martin ≤2, none >4, all baseline mRS ≤1); generalisability to larger/higher-grade AVMs is uncertain.
Modest enrolment yield: 226 randomised of 1740 screened (13%); 63% of eligible patients agreed to randomisation — selection bias possible.
Definition of symptomatic stroke included new-onset headache with imaging changes, which could differentially capture events in interventional patients undergoing more surveillance imaging.
No standardisation of interventional technique across sites — investigators used usual practice, so results reflect real-world heterogeneity rather than a single defined intervention.

Funding

National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS/NIH). The funder participated in study design, data interpretation, and writing of the report, but had no role in data collection or data analysis.

Based on: ARUBA (Lancet, 2014)