Letters

The low-density lipoprotein levels of patients with FH at follow-up did not meet current treatment standards and carotid IMT was thicker than in unaffected siblings. More robust lipid-lowering therapy or earlier initiation of statins may be required to completely restore arterial wall morphology and avert cardiovascular events later in life in this high-risk population. D. Meeike Kusters, MD Hans J. Avis, MD, PhD Eric de Groot, MD, PhD Frits A. Wijburg, MD, PhD John J. P. Kastelein, MD, PhD Albert Wiegman, MD, PhD Barbara A. Hutten, PhD, MSc

1. Marks D, Thorogood M, Neil HA, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168(1):1-14. 2. Wiegman A, de Groot E, Hutten BA, et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004;363 (9406):369-370. 3. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics. 2011;128 (suppl 5):S213-S256. 4. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA. 2004;292(3):331-337. 5. de Groot E, Hovingh GK, Wiegman A, et al. Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation. 2004;109(23) (suppl 1):III33-III38.

Author Affiliations: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands (Kusters, Avis, Kastelein); Department of Imagelabonline and Imagelabcardiovascular, University of Amsterdam, Amsterdam, the Netherlands (de Groot); Department of Pediatrics, Academic Medical Center, Amsterdam, the Netherlands (Wijburg, Wiegman); Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands (Hutten). Corresponding Author: Barbara A. Hutten, PhD, MSc, Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands ([email protected] .uva.nl). Author Contributions: Drs Kusters and Hutten had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wiegman and Hutten share last authorship position in the byline. Study concept and design: Avis, Kastelein, Hutten. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Kusters, Avis, Hutten. Critical revision of the manuscript for important intellectual content: Avis, de Groot, Wijburg, Kastelein, Wiegman, Hutten. Statistical analysis: Kusters, de Groot, Hutten. Obtained funding: Avis, Hutten. Administrative, technical, or material support: Kusters, Avis, de Groot, Kastelein, Hutten. Study supervision: Wijburg, Kastelein, Wiegman, Hutten. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kastelein reported being a recipient of the Lifetime Achievement Award of the Netherlands Heart Foundation (project number 2010T082); and receiving lecture grants from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, ISiS, Merck Sharp Dohme, Novartis, Pfizer, Regeneron, Roche, and sanofi. No other disclosures were reported. Funding/Support: The AfterTen study is supported by grant 2009B059 from the Dutch Heart Foundation. Role of the Funder/Sponsor: The Dutch Heart Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We are grateful to all children who participated in this study. We would also like to thank Johan Gort, BSc (Department of Vascular Medicine, Academic Medical Center), for performing all ultrasound measurements; Harry R. Büller, MD, PhD (Department of Vascular Medicine, Academic Medical Center), for reading the manuscript and providing comments; and the following members of the AfterTen study group for their help with the grant application (Maud N. Vissers, PhD, Department of Vascular Medicine, Academic Medical Center), interpretation of safety parameters (A. S. Paul van Trotsenburg, MD, PhD, Department of Pediatrics, Academic Medical Center), and assessment of compliance (Ellen M. Smets, PhD, Department of Medical Psychology, Academic Medical Center). None of the persons named received compensation for their contributions to the study.

6. Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-1278.

COMMENT & RESPONSE

Conservative Management vs Intervention for Unruptured Brain Arteriovenous Malformations To the Editor Management of brain arteriovenous malformations (bAVMs) has been debated in the recent medical literature. If left untreated, bAVMs confer a risk of neurological morbidity and mortality; however, treatment is associated with risks but offers the potential for lifetime eradication. Dr Al-Shahi Salman and colleagues1 prospectively followed up 204 patients with unruptured bAVMs over 12 years. Morbidity and mortality rates among patients managed conservatively vs those who underwent interventions (surgical resection, endovascular treatment, radiosurgery, or multimodal intervention) were compared. Over a 4-year period, the authors reported 36 events leading to sustained disability or death in the conservative management group vs 39 in the intervention group. The number of bAVMassociated symptomatic strokes or deaths in patients managed conservatively vs with an intervention was 14 vs 38, respectively. Al-Shahi Salman et al1 documented an AVM obliteration rate of 66%, a poor outcome given that 90% of the treated bAVMs were of low grade. This rate is likely an overestimation because some treatment results were documented only with magnetic resonance imaging, a study that does not provide certainty of a cure. In comparison, a meta-analysis2 of 13 698 patients documented a surgical obliteration rate of 96% for low-grade bAVMs. Complication rates in the intervention group of this study were high at 27.1% compared with 5.7% reported in the meta-analysis.2 Al-Shahi Salman et al1 did not disclose the timeline of hemorrhages in the intervention group, especially among incompletely treated bAVMs. In addition, 20 of 31 deaths (64%) in the conservative management group were classified as unrelated to the bAVM, and given the limited information on the cause of death, it is possible that a portion of the deaths in this cohort was related to AVM rupture. The fact that AVM rupture

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was not proven does not mean that the AVM did not bleed and was not the cause of death. Furthermore, longer follow-up would result in increased number of bleeds in the conservative management group while the obliterated bAVMs should have a low rate of additional bleeds, altering the risk-benefit balance in the study. Given the high complication rate in the treatment cohort, the low cure rate, and the undefined causes of death in the conservatively managed patients, it is not possible to conclude that conservative management is superior to intervention in patients with bAVM. Gregory M. Weiner, MD Ramesh Grandhi, MD Robert M. Friedlander, MD Author Affiliations: Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Corresponding Author: Robert M. Friedlander, MD, University of Pittsburgh Medical Center, Neurological Surgery, 200 Lothrop St, Ste B400, Pittsburgh, PA 15213 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Friedlander reported receiving a grant from the National Institutes of Health and consulting for Best Doctors. No other disclosures were reported. 1. Al-Shahi Salman R, White PM, Counsell CE, et al; Scottish Audit of Intracranial Vascular Malformations Collaborators. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661-1669. 2. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011-2019.

To the Editor Dr Al-Shahi Salman and colleagues1 concluded that conservative management for bAVMs was superior to intervention for up to 12 years based on a prospective, populationbased inception cohort study. The lack of detail regarding secondary outcomes, a high mortality rate in the conservatively managed group, and substandard interventions may undermine the authors’ conclusions. First, little information was provided regarding the details of the secondary outcomes. There is no way to determine whether the patients in the intervention group achieved secondary outcomes before or after obliteration of their bAVM. No protection is afforded from intervention until a bAVM is completely obliterated.2 Second, interventions used in the intervention group are not in agreement with current treatments. A pooled analysis indicates that Spetzler-Martin grade I and II bAVMs are best treated with microsurgical resection.3 However, less than 32% of all bAVMs in this study received microsurgical resection despite 55% of the patients harboring Spetzler-Martin grade I and II bAVMs. Furthermore, 21.4% of patients were treated with endovascular therapy alone, which is currently not considered to be a curative procedure.4 The most impressive data from the study are the primary outcomes. Among patients managed conservatively who were included in the analysis of primary outcomes, 31 of 98 (31.6%) died (11 [11.2%] of which were possibly because of their bAVMs) compared with 10 of 103 (9.7%) deaths in the intervention group 1058

(4 [3.8%] of which were possibly because of their bAVMs). The authors attributed the higher mortality rate in the conservative management group to the imbalance in age between the 2 groups at baseline. However, no details are provided regarding the non–AVM-related deaths. The mean age at inception in the conservative management group was 53 years, and with a median follow-up of 5.2 years, a mortality rate of 31.6% appears extremely high. Without further details, the only conclusion that can be drawn from the data provided by Al-Shahi Salman et al1 is that conservatively managed patients with bAVMs have a higher mortality rate as well as a higher mortality rate from bAVMrelated causes compared with patients undergoing intervention. Hasan A. Zaidi, MD Jonathan J. Russin, MD Robert F. Spetzler, MD Author Affiliations: Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona. Corresponding Author: Robert F. Spetzler, MD, Neuroscience Publications, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, 350 W Thomas Rd, Phoenix, AZ 85013 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Al-Shahi Salman R, White PM, Counsell CE, et al; Scottish Audit of Intracranial Vascular Malformations Collaborators. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661-1669. 2. Miyamoto S, Hashimoto N, Nagata I, et al. Posttreatment sequelae of palliatively treated cerebral arteriovenous malformations. Neurosurgery. 2000; 46(3):589-594. 3. Spetzler RF, Ponce FA. A 3-tier classification of cerebral arteriovenous malformations. J Neurosurg. 2011;114(3):842-849. 4. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011-2019.

In Reply Neurosurgical colleagues have raised issues about our study comparing conservative management and intervention for unruptured bAVMs that do not invalidate our findings but instead provide an opportunity to give more detail, correct misinterpretations, and reemphasize the hierarchy of evidence.1 First, it is unlikely that some of the “other” deaths in the conservative group were related to untreated bAVMs. Every death was adjudicated with all available clinical, radiographic, and pathological information. The 26 other deaths were due to cancer (n = 9), infection (n = 6), cardiovascular disease (n = 5), ischemic stroke unrelated to bAVM (n = 4), subdural hematoma unrelated to bAVM (n = 1), and drug overdose (n = 1). Dr Zaidi and colleagues note that 4 deaths in the intervention group and 11 deaths in the conservative group were possibly due to bAVM. Given that we did not prespecify this comparison, a post hoc comparison should be interpreted cautiously; we will continue to monitor deaths. Second, Dr Weiner and colleagues and Dr Zaidi and colleagues question the timing of secondary outcomes in rela-

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tion to evidence of bAVM obliteration. Of the 50 first, second, or third occurrences of secondary outcomes following intervention, 19 occurred in patients who never had evidence of obliteration, 26 before obliteration occurred, and 5 after obliteration. Because the majority of these outcomes occurred before or after obliteration, and the risk of incurring a secondary outcome while attempting to achieve bAVM obliteration with intervention outweighed the risk of conservative management over 12 years, the benefits of intervention remain to be proven. Third, the authors of both letters suggest that the interventions in this population-based study were substandard bec ause bAVM obliteration was infrequent. A metaregression analysis2 found that a median of 96% of bAVMs were obliterated after microsurgery in published case series (which may have been subject to selection, publication, and partial verification biases), while in our cohort, 29 of 31 (94%) undergoing microsurgical excision and follow-up imaging achieved obliteration. Proportions of bAVMs obliterated after stereotactic radiosurgery and embolization in our cohort exceeded the medians reported in the metaregression analysis. Weiner and colleagues compare our cohort’s 1-year complication rate with the meta-regression analysis,2 but studies in the latter did not record cerebral infarcts or focal neurological deficits, lacked independent prospective assessment, and may have been influenced by publication bias. However, A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA)3 identified outcomes in a similar way as our cohort and its findings agreed with ours. Zaidi and colleagues suggest that endovascular therapy alone is currently not considered to be a curative procedure, yet bAVM obliteration occurred in 45% of people selected for embolization alone in our cohort, similar to recent case series. Given the range of treatments used for unruptured bAVMs in our study and in ARUBA,3 international consensus on the use of microsurgery seems to be less than suggested in the letters. In addition, the hierarchy of evidence1 dictates that clinical practice should be guided by a study’s risk of bias. In this case, the findings of a randomized trial (level 2)3 and a nonrandomized controlled cohort study (level 3) concur and are more reliable than case series without a comparison group or independent outcome assessment, potentially subject to selection and publication biases (level 4). Rustam Al-Shahi Salman, PhD Carl E. Counsell, MD Philip M. White, FRCR Author Affiliations: Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, Scotland (Al-Shahi Salman); Division of Applied Health Sciences, University of Aberdeen, Aberdeen, Scotland (Counsell); Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, England (White). Corresponding Author: Rustam Al-Shahi Salman, PhD, Division of Clinical Neurosciences, University of Edinburgh, Bramwell Dott Building, Western General Hospital, Edinburgh EH4 2XU, Scotland ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Al-Shahi Salman reported receipt of grants from the Medical Research Council, the Stroke Association, and the Chief Scientist Office of the Scottish Government.

Dr White reported receipt of grants and personal fees from Covidien, Codman, and Microvention Terumo during the conduct of the study. No other disclosures were reported. 1. University of Oxford Centre for Evidence-Based Medicine. OCEBM levels of evidence. http://www.cebm.net/ocebm-levels-of-evidence/. Accessed June 2, 2014. 2. van Beijnum J, van der Worp HB, Buis DR, et al. Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA. 2011;306(18):2011-2019. 3. Mohr JP, Parides MK, Stapf C, et al; International ARUBA Investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014;383(9917):614-621.

Idiopathic Intracranial Hypertension To the Editor The Idiopathic Intracranial Hypertension Treatment Trial1 evaluated the use of acetazolamide vs placebo in conjunction with a weight-reducing, low sodium diet in adults with idiopathic intracranial hypertension (IIH). Although the authors stated “there are no properly designed clinical trials,” the widespread use of acetazolamide has been questioned since the results of the first randomized controlled trial2 that did not demonstrate benefit of acetazolamide in IIH, although it was underpowered. The trial demonstrated a small difference in the primary outcome measure, the perimetric mean deviation (PMD), in the acetazolamide vs placebo cohorts (0.71 dB [95% CI, 0-1.43 dB]; P = .05). The sample size was not powered to detect this small a difference, almost half that originally predicted (1.3 dB) and defined a priori as the minimal clinically meaningful difference. Consequently, the results must be seen as hypothesis generating only. There was no significant difference in lumbar puncture pressure, headache disability, or visual acuity between the 2 groups. However, adverse events (nausea, paresthesia, and diarrhea) and drug discontinuation were significantly higher in the acetazolamide group. The latter may reflect the high doses given in the study (>40% were taking 4 g of acetazolamide). A prospective cohort study3 established that weight loss is an effective disease-modifying therapy in IIH, with patients who followed a 3-month low-calorie diet having significantly reduced intracranial pressure compared with pressure measured in the 3 months before the diet, as well as improved symptoms and reduced papilledema. In the current trial,1 the acetazolamide group lost significantly more weight than the placebo group (−4.05 kg [95% CI, −6.27 to −1.83 kg]; P < .001). We believe that this potentially relates to the anorexigenic adverse event profile of acetazolamide. Thus weight loss may be the reason for the small improvement in the acetazolamide cohort despite the findings from their mediation model analysis, which we believe may have been misinterpreted.4 When the analysis was adjusted for weight change, differences between treatment groups were nonsignificant (0.03 dB [95% CI, −0.10 to 0.16 dB]; P = .64). Consequently, we are unable to understand why weight was not considered a mediating factor. It is difficult to interpret what new information the Idiopathic Intracranial Hypertension Treatment Trial provides

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Conservative management vs intervention for unruptured brain arteriovenous malformations.

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