RESUMO
BACKGROUND: Treating unruptured brain arteriovenous malformations (bAVMs) represent significant challenges, with numerous uncertainties still in debate. The ARUBA trial induced further investigation into optimal management strategies for these lesions. Here, we present a systematic-review and meta-analysis focusing on ARUBA-eligible studies, aiming to correlate patient data with outcomes and discuss key aspects of these studies. METHODS: Following PRISMA guidelines, we conducted a systematic-review. Variables analyzed included bAVM Spetzler-Martin (SM) grade, treatment modalities, and outcomes such as mortality and neurological deficits. We compared studies with a minimum of 50% cases classified as SM 1-2 lesions and those with less than 50% in this category. Similarly, a comparison between studies with at least 50% microsurgery-cases and those with less than 50% was performed. We examined correlations between mortality incidence, SM distribution, and treatment modalities. RESULTS: Our analysis included 16 studies with 2.417 patients. The frequency of bAVMs SM-grade 1-2 ranged from 44% to 76%, SM-grade 3 from 19% to 48%, and SM 4-5 from 5 to 23%. Notably, studies with more than 50% cases presenting lesions SM-grade 1-2 presented significantly lower mortality rates than those with less than 50% cases of SM 1-2 lesions (P < 0.001). No significant difference in mortality rates or neurological deficits was identified between studies with more than 50% of microsurgery-cases and those with less than 50%. CONCLUSIONS: The analysis revealed that studies with a higher proportion of bAVMs presenting SM 1-2 lesions were associated with lower mortality rates. Mortality did not show a significant association with treatment modalities.
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Malformações Arteriovenosas Intracranianas , Humanos , Malformações Arteriovenosas Intracranianas/cirurgia , Malformações Arteriovenosas Intracranianas/mortalidade , Malformações Arteriovenosas Intracranianas/terapia , Microcirurgia , Procedimentos NeurocirúrgicosRESUMO
Brain arteriovenous malformations (bAVMs) are vascular lesions that carry significant morbidity and mortality risk upon rupture. bAVM rupture causes either intracerebral or intraventricular hemorrhage, or both. In 2014, the first results of the ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) were published in The Lancet, causing a paradigm shift in clinical practice and suggesting the superiority of medical treatment in terms of mortality or stroke compared with any intervention designed to obliterate the AVM. In 2020, the final results of the ARUBA trial were published. In this Viewpoint, we critically review the clinical equipoise behind the trial, highlight issues regarding external validity, and place the results of the trial in the context of other results in scientific literature of bAVMs using Bayesian inference. ARUBA is a trial of decision-making, and only proper knowledge of the nuances of its interpretation within the broader context of bAVM research can lead to proper decision-making when confronted with patients with unruptured bAVMs.
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Malformações Arteriovenosas Intracranianas/complicações , Teorema de Bayes , Hemorragia Cerebral/etiologia , Tomada de Decisão Clínica , Humanos , Malformações Arteriovenosas Intracranianas/epidemiologia , Malformações Arteriovenosas Intracranianas/mortalidade , Prevalência , Ruptura , Acidente Vascular Cerebral/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. METHODS: ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. FINDINGS: Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference -19·76, 95% CI -30·33 to -9·19). INTERPRETATION: After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. FUNDING: National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.
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Fístula Arteriovenosa/tratamento farmacológico , Fístula Arteriovenosa/cirurgia , Malformações Arteriovenosas Intracranianas/tratamento farmacológico , Malformações Arteriovenosas Intracranianas/cirurgia , Adulto , Fístula Arteriovenosa/mortalidade , Embolização Terapêutica/métodos , Feminino , Seguimentos , Humanos , Malformações Arteriovenosas Intracranianas/mortalidade , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/métodos , Radiocirurgia/métodos , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
Brain arteriovenous malformations (AVMs) are complex and heterogeneous lesions that can rupture, causing significant morbidity and mortality. While ruptured lesions are usually treated, the management of unruptured AVMs remains unclear. A Randomized trial of Unruptured Brain Arteriovenous Malformations (ARUBA) was the first trial conducted to compare the effects of medical and interventional therapy. Although it concluded that medical therapy was superior in preventing stroke and death over a follow-up period of 33 months, the findings were met with intense criticism regarding several aspects of study design, progression, and analysis/conclusion. Namely, the increased use of stand-alone embolisation relative to microsurgery in a cohort with predominantly low-grade lesions combined with a short follow-up period amplified treatment risk. Subsequently, several observational studies were conducted on ARUBA-eligible patients to investigate the safety and efficacy of microsurgery, radiosurgery, and endovascular embolisation over longer follow-up periods. These reports showed that favourable safety profiles and cure rates can be achieved with appropriate patient selection and judicious use of different treatment modalities in multidisciplinary centres. Since large prospective randomised trials on AVMs may not be feasible, it is important to make use of practice-based data beyond the flawed ARUBA study to optimise patients' lifetime outcomes.
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Embolização Terapêutica , Procedimentos Endovasculares , Malformações Arteriovenosas Intracranianas/terapia , Microcirurgia , Radiocirurgia , Acidente Vascular Cerebral/prevenção & controle , Circulação Cerebrovascular , Tomada de Decisão Clínica , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Medicina Baseada em Evidências , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/mortalidade , Malformações Arteriovenosas Intracranianas/fisiopatologia , Microcirurgia/efeitos adversos , Microcirurgia/mortalidade , Radiocirurgia/efeitos adversos , Radiocirurgia/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: A randomized trial of unruptured brain arteriovenous malformations (ARUBA) reported superior outcomes in conservative management compared to interventional treatment. There were numerous limitations to the study. This study aimed to investigate the efficacy of gamma knife radiosurgery (GKS) for patients with brain arteriovenous malformations (AVMs) by comparing its outcomes to those of the ARUBA study. METHODS: We retrospectively reviewed ARUBA-eligible patients treated with GKS from June 2002 to September 2017 and compared against those in the ARUBA study. AVM obliteration and hemorrhage rates, and clinical outcomes following GKS were also evaluated. RESULTS: The ARUBA-eligible cohort comprised 264 patients. The Spetzler-Martin grade was Grade I to II in 52.7% and III to IV in 47.3% of the patients. The mean AVM nidus volume, marginal dose, and follow-up period were 4.8 cm³, 20.8 Gy, and 55.5 months, respectively. AVM obliteration was achieved in 62.1%. The annual hemorrhage rate after GKS was 3.4%. A stroke or death occurred in 14.0%. The overall stroke or death rate of the ARUBA-eligible cohort was significantly lower than that of the interventional arm of the ARUBA study (P < 0.001) and did not significantly differ from that of the medical arm in the ARUBA study (P = 0.601). CONCLUSION: GKS was shown to achieve a favorable outcome with low procedure-related morbidity in majority of the ARUBA-eligible patients. The outcome after GKS in our patients was not inferior to that of medical care alone in the ARUBA study. It is suggested that GKS is rather superior to medical care considering the short follow-up duration of the ARUBA study.
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Hemorragia/etiologia , Malformações Arteriovenosas Intracranianas/cirurgia , Radiocirurgia/efeitos adversos , Acidente Vascular Cerebral/etiologia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Malformações Arteriovenosas Intracranianas/mortalidade , Malformações Arteriovenosas Intracranianas/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: The results of the A Randomized Trial of Unruptured Brain Arteriovenous (ARUBA) study, indicating that conservative medical management of unruptured brain arteriovenous malformations (UBAVM) is superior to interventional therapy, have generated debates that have hampered their application into clinical practice. Irrespectively of study conclusions, it seems reasonable to explore how much better interventional therapy would have to be to become competitive with conservative medical management. METHODS: We conducted an exploratory analysis to replicate the original data from ARUBA. The functional form of the replicated ARUBA data, according to their Weibull distribution, allowed estimation of parameters. We carried out Monte Carlo simulations while introducing theoretical reductions of interventional risk, and the results were used to construct theoretical and example Kaplan-Meier curves from simulations. RESULTS: The "ARUBA Replication" analysis showed results nearly identical to those published in the study, with an estimated hazard ratio of 0.27 (95% CI: 0.14-0.55). At 50% interventional risk reduction, the simulations showed an estimated event rate of 14.9%, and the protective effect of conservative medical management was no longer statistically significant. Greater risk reductions hastened the time to benefit for interventional therapy, and an 80% risk reduction demonstrated superiority of interventional therapy at just over 2 years Hazard Ratio (HR: 1.44, 95% CI: 0.55-4.92). CONCLUSIONS: Reduction in risk of interventional therapy by 50%-80% results in more competitive clinical outcomes, equating or surpassing the benefit of conservative medical management of UBAVM. This conjecture should be taken into consideration in the design of future studies of this patient population, particularly because it is supported by recent observational studies.
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Tratamento Conservador , Procedimentos Endovasculares , Malformações Arteriovenosas Intracranianas/terapia , Modelos Teóricos , Procedimentos Neurocirúrgicos , Tomada de Decisão Clínica , Simulação por Computador , Tratamento Conservador/efeitos adversos , Tratamento Conservador/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/mortalidade , Método de Monte Carlo , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/mortalidade , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE The authors of this study found that, given the latency period required for arteriovenous malformation (AVM) obliteration after stereotactic radiosurgery (SRS), a study with limited follow-up cannot assess the benefit of SRS for unruptured AVMs. METHODS The authors reviewed their institutional experience with "ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)-eligible" AVMs treated with SRS between 1987 and 2016, with the primary outcome defined as stroke (ischemic or hemorrhagic) or death (AVM related or AVM unrelated). Patients with at least 3 years of follow-up in addition to those who experienced stroke or died during the latency period were included. Secondary outcome measures included obliteration rates, patients with new seizure disorders, and those with new focal deficits without stroke. RESULTS Of 233 patients included in this study, 32 had a stroke or died after SRS over the mean 8.4-year follow-up (14%). Utilizing the 10% stroke or death rate at a mean 2.8-year follow-up for untreated AVMs in ARUBA, the rate in the authors' study is significantly lower than that anticipated at the 8.4-year follow-up for an untreated cohort (14% vs 30%, p = 0.0003). Notwithstanding obliteration, in this study, annualized rates of hemorrhage and stroke or death after 3 years following SRS were 0.4% and 0.8%, respectively. The overall obliteration rate was 72%; new seizure disorders, temporary new focal deficits without stroke, and permanent new focal deficits without stroke occurred in 2% of patients each. CONCLUSIONS After a sensible follow-up period exceeding the latency period, there is a lower rate of stroke/death for patients with treated, unruptured AVMs with SRS than for patients with untreated AVMs.
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Malformações Arteriovenosas Intracranianas/cirurgia , Procedimentos Neurocirúrgicos , Radiocirurgia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/mortalidade , Hemorragias Intracranianas/epidemiologia , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/mortalidade , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Convulsões/etiologia , Acidente Vascular Cerebral/etiologia , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: In light of evidence from ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations), neurovascular specialists had to reconsider deliberate treatment of unruptured brain arteriovenous malformations (uBAVMs). Our objective was to determine the outcomes of uBAVM treated with primary embolization using ethylene vinyl alcohol (ONYX). METHODS: Patients with uBAVM who met the inclusion criteria of ARUBA and were treated with primary Onyx embolization were assigned to this retrospective study. The primary outcome was the modified Rankin Scale score. Secondary outcomes were stroke or death because of uBAVM or intervention and uBAVM obliteration. RESULTS: Sixty-one patients (mean age, 38 years) were included. The median observation period was 60 months. Patients were treated by embolization alone (41.0%), embolization and radiosurgery (57.4%), or embolization and excision (1.6%). Occlusion was achieved in 44 of 57 patients with completed treatment (77.2%). Forty-seven patients (77.1%) had no clinical impairment at the end of observation (modified Rankin Scale score of <2). Twelve patients (19.7%) reached the outcome of stroke or death because of uBAVM or intervention. Treatment-related mortality was 6.6% (4 patients). CONCLUSIONS: In uBAVM, Onyx embolization alone or combined with stereotactic radiosurgery achieves a high occlusion rate. Morbidity remains a challenge, even if it seems lower than in the ARUBA trial.
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Embolização Terapêutica/métodos , Malformações Arteriovenosas Intracranianas/terapia , Polivinil , Tantálio , Adulto , Terapia Combinada , Combinação de Medicamentos , Embolização Terapêutica/mortalidade , Feminino , Seguimentos , Humanos , Malformações Arteriovenosas Intracranianas/complicações , Malformações Arteriovenosas Intracranianas/mortalidade , Masculino , Complicações Pós-Operatórias , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Estudos Retrospectivos , Ruptura , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Resultado do TratamentoRESUMO
OBJECTIVES: To determine the outcome of microsurgical excision of selected unruptured brain arteriovenous malformations (AVMs), and to compare the results with those of the ARUBA trial. METHODS: Prospective data collection for all patients undergoing microsurgical excision of unruptured brain AVMs by two neurovascular surgeons. Outcome measures similar to those assessed in the ARUBA trial (death and stroke) as well as modified Rankin scores (mRS) at 6 months were assessed. RESULTS: Between September 2004 and September 2014, 45 patients with unruptured brain AVMs underwent microsurgical excision. 11 patients (eight children and three with mRS >2 at presentation) were excluded to match ARUBA eligibility criteria. 34 patients were included in this study. AVM characteristics closely matched those in the ARUBA trial with 70.5% Spetzler-Martin (SM) grade I or II AVMs, 68% AVM size <3 cm. However, compared to ARUBA, a larger proportion of our patients presented with seizures, and a lower proportion with headaches. 8(23%) had preoperative embolization. There were no deaths and no strokes (as defined in ARUBA). 5 (14.7%) had permanent neurological deficit related to surgery within/near eloquent cortex. At 6 months follow-up, 32 (94%) had mRS score of 0-1. Two (6%) had mRS 2 and none had mRS> 2. Postoperative digital DSA confirmed complete AVM excision in all cases. None of the patients have suffered intracranial hemorrhage during the follow-up period of 6-126 (median 69) months. CONCLUSIONS: Microsurgical excision of unruptured brain AVMs can be performed with low morbidity in selected cases. Our study has limitations particularly the small number of patients with selected AVMs for microsurgical excision. However, our results suggest that ARUBA results may not be applicable to microsurgical excision when cases are appropriately selected for this treatment modality.
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Malformações Arteriovenosas Intracranianas/cirurgia , Microcirurgia/métodos , Procedimentos Neurocirúrgicos/métodos , Adulto , Angiografia Digital , Embolização Terapêutica , Feminino , Seguimentos , Cefaleia/etiologia , Humanos , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/mortalidade , Masculino , Microcirurgia/efeitos adversos , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/etiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Radiocirurgia , Convulsões/etiologia , Acidente Vascular Cerebral/etiologia , Resultado do TratamentoRESUMO
INTRODUCTION: It is debatable whether pediatric patients diagnosed with arteriovenous malformations (AVMs) should be treated as adults. Several indexes to classify AVMs have been proposed in the literature, and most try to predict the outcome for each specific treatment. The indexes differ in the variables considered, but they are all based in adult populations. In this study, we analyzed the variables that influence the obliteration time and probability of occurrence in a Mexican pediatric population diagnosed with an AVM and treated with stereotactic radiosurgery (SRS). METHODS: We analyzed 45 pediatric patients (<18 years) with a minimum follow-up of 10 months and a maximum of 112 months. We used logistic regression analysis and Kaplan-Meier curves to evaluate the influence of age, AVM volume, prescribed dose, minimum dose, maximum dose, time of follow-up, sex, previous hemorrhage, venous drainage, treatment technique, previous treatment and location. We also evaluated the predictive power of the following indexes: Spetzler-Martin, RBAS, or K index dose deviation. RESULTS: We found that the radiation technique used may influence the obliteration occurrence (p=0.057). The data suggests that circular arcs are a more efficient treatment technique than dynamic arcs. However, no relationship of dose or volume with treatment technique could be found. Obliteration was also dependent on follow-up time and after three years of follow-up, the obliteration probability decreases (p=0.024). According to Kaplan-Meier analysis, the nidus obliteration time was related with the location according to the Spetzler-Martin index. If the nidus was located in a non-eloquent region, there was a tendency of a shorter obliteration time (p=0.071). CONCLUSION: None of the previously proposed indexes for adults predict obliteration in this pediatric population. Treatment technique, eloquence and follow up time were the only variables that showed influence in obliteration. Since the highest probability of obliteration occurs during the first three years, if the nidus has not been obliterated after this time then another treatment option could be considered.