Comprehensive Aneurysm Management (CAM): An All-Inclusive Care Trial for Unruptured Intracranial Aneurysms

doi:10.1016/j.wneu.2020.06.018

World Neurosurgery

Volume 141, September 2020, Pages e770-e777

https://doi.org/10.1016/j.wneu.2020.06.018 Get rights and content

Background

In the absence of randomized evidence, the optimal management of patients with unruptured intracranial aneurysms (UIA) remains uncertain.

Methods

Comprehensive Aneurysm Management (CAM) is an all-inclusive care trial combined with a registry. Any patient with a UIA (no history of intracranial hemorrhage within the previous 30 days) can be recruited, and treatment allocation will follow an algorithm combining clinical judgment and randomization. Patients eligible for at least 2 management options will be randomly allocated 1:1 to conservative or curative treatment. Minimization will be used to balance risk factors, using aneurysm size (≥7 mm), location (anterior or posterior circulation), and age <60 years.

Results

The CAM primary outcome is survival without neurologic dependency (modified Rankin Scale [mRS] score <3) at 10 years. Secondary outcome measures include the incidence of subarachnoid hemorrhage during follow-up and related morbidity and mortality; morbidity and mortality related to endovascular treatment or surgical treatment of the UIA at 1 year; overall morbidity and mortality at 1, 5, and 10 years; when relevant, duration of hospitalization; and, when relevant, discharge to a location other than home. The primary hypothesis for patients randomly allocated to at least 2 options, 1 of which is conservative management, is that active UIA treatment will reduce the 10-year combined neurologic morbidity and mortality (mRS score >2) from 24% to 16%. At least 961 patients recruited from at least 20 centers over 4 years will be needed for the randomized portion of the study.

Conclusions

Patients with unruptured intracranial aneurysms can be comprehensively managed within the context of an all-inclusive care trial.

Introduction

The best approach to managing patients with unruptured intracranial aneurysms (UIAs) is currently uncertain. The prevalence of intracranial aneurysms has been estimated at 1%–5% of the adult population.¹^,² With the increasing availability of noninvasive imaging of the brain, UIAs are increasingly being discovered during the investigation of unrelated symptoms in an aging population.

Most aneurysms remain asymptomatic unless they rupture, an event that occurs infrequently (annual incidence of 5–10/100,000).³ The annual risk of bleeding from incidentally discovered aneurysms is debated, but most series and meta-analyses have reported a low rate between 0.1% and 2%.4, 5, 6, 7, 8, 9 Although subarachnoid hemorrhage (SAH) is associated with a high morbidity and mortality (45%–75%), preventive treatments also carry risk. It would seem essential to preemptively treat those patients deemed to be at risk for rupture to prevent the morbidity and mortality associated with SAH. On the other hand, many patients diagnosed with UIAs may never suffer SAH, and it is imperative to avoid iatrogenic injuries to patients “destined to coexist peacefully with their unruptured lesions.”¹⁰

The time-honored approach to treating UIAs is with microsurgical clipping, which involves excluding the aneurysm from the circulation by placing a metallic clip across the aneurysm neck. Surgical clipping is widely considered a safe and durable means to treat UIAs, but in recent years it is being increasingly replaced by endovascular treatment (EVT).¹¹

An international randomized controlled trial (RCT) on ruptured aneurysms (ISAT) and the Barrow Randomized Aneurysm Trial (BRAT) have shown that EVT is associated with improved outcomes of patients treated after SAH compared with surgical clipping, but this finding cannot be extrapolated to unruptured lesions.¹²^,¹³

The efficacy of endovascular treatment in the preventing aneurysm rupture remains unknown.14, 15, 16 Some observational studies and registries have suggested that immediate treatment-related risks for UIA are lower with EVT than with surgical clipping,¹⁷ but EVT may be less effective than surgery due to long-term angiographic recurrences.¹⁸

Meta-analyses of the safety and efficacy of surgical and endovascular management of UIAs have been conducted. The overall quality of the literature on the subject is poor, with no justification for preventive treatments for most patients. Surgical clipping was associated with a risk of unfavorable outcome of 6.7% (99% confidence interval [CI], 4.9%–9.0%) and a risk of death of 1.7% (99% CI, 0.9%–3.0%).¹⁹^,²⁰ Endovascular treatment was associated with a risk of unfavorable outcome of 4.8% (99% CI, 3.9% to 6.0%) and a risk of death of 2.0% (99% CI, 1.5%–2.6%).²¹^,²² Neither surgery nor EVT has proven superior to conservative management,²³ yet both endovascular and surgical treatments are performed in large numbers of patients daily without evidence that they are doing more good than harm and without evidence that one approach is superior to the other. There is currently no scientific evidence to support treatment of UIAs, and there are no well-accepted guidelines.²⁴ Several prospective registries comparing patients selected for medical management with patients selected for surgical management constitute the most significant studies on UIAs.²⁵ Unfortunately, these efforts suffer from systematic biases, a consequence of the current “best clinical judgment” approach to managing these patients. Patients recruited in these studies were selected in such a fashion that those considered at low treatment risk and at high risk for rupture were offered treatment; only those patients at low risk for rupture, or with comorbid conditions making treatment unadvisable, were included in the “natural history” group.25, 26, 27, 28, 29

The uncertainty regarding the management of UIAs has not progressed in the last 30 years. Time alone and observational cohort studies of treated or untreated patients cannot provide a valid answer to the fundamental question regarding whether or not they should be treated. The fundamental ethical basis for the present study is that physicians should offer a risky preventive treatment only when it has been shown to be beneficial. Before such time, UIA treatment should be offered as an RCT, giving the patient a 50% chance of receiving a treatment aimed at preventing SAH and an equal 50% chance of avoiding the potential complications of treatment.³⁰ In the presence of uncertainty, a care trial is the best way to address the question of whether patients with UIAs are best managed medically until definite indications arise or with endovascular or surgical treatment.

This study addresses the problem of multiple management alternatives by offering an all-inclusive framework trial that combines clinical judgment and randomized allocation, as inspired by a successfully recruiting, similarly all-inclusive study on brain arteriovenous malformations.³¹

Section snippets

Objectives

The general objective is to use CAM to provide a care research framework for managing all patients with UIAs.³⁰ For patients for whom conservative management is contemplated, CAM may validate previous observational studies that claim a very low risk of rupture. The registry portion of CAM could also serve as a source of patients for secondary trials to assess the value of imaging follow-up studies or various pharmaceutical agents to prevent ruptures (e.g., aspirin, statins). For patients for

Methods

This study has been registered with ClinicalTrials.gov (identifier NCT04155606).

Discussion

UIAs are being increasingly discovered, and an ethical, rational means to help physicians properly manage affected patients is needed. Two recently elaborated scoring systems have proposed expedient answers to the clinical dilemma, but neither offers a satisfactory solution. The PHASES (Population, Hypertension, Age, Size, Earlier subarachnoid hemorrhage, Site of aneurysm) score is based on the reanalysis of past case series reporting the risk of rupture of aneurysms in patients selected for

Conclusion

CAM is designed to offer a care research context to manage UIA patients in the presence of uncertainty.

CRediT authorship contribution statement

Tim E. Darsaut: Conceptualization, Methodology, Resources, Writing - original draft, Supervision. Hubert Desal: Writing - review & editing. Christophe Cognard: Writing - review & editing, Writing - review & editing. Anne-Christine Januel: Writing - review & editing. Romain Bourcier: Writing - review & editing. Grégoire Boulouis: Writing - review & editing. Jai Jai Shiva Shankar: Conceptualization, Methodology, Resources, Writing - original draft, Writing - review & editing. J. Max Findlay:

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Understanding how the primary endpoint impacts the interpretation of trial results: The Japanese Adult Moyamoya bypass trial
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The meaning of a clinical trial depends to a large extent on the choice of the primary outcome measure, which can be explanatory or pragmatic.
We review the Japanese Adult Moyamoya (JAM) trial, that compared surgical extracranial to intracranial (EC-IC) bypass and medical management of hemorrhagic moyamoya disease. We also review some principles which guide the selection of the primary trial endpoint.
The main component of the primary outcome measure in JAM was rebleeding, a surrogate outcome that allowed investigators to demonstrate that surgical bypass had causal efficacy. However, the number of patients with a poor outcome, defined as those with a modified Rankin score (mRS) > 2, would have been a more pragmatic choice. Unfortunately, the trial was too small to show that patients benefited from surgery.
The JAM trial showed that EC-IC bypass can decrease rebleeding in moyamoya patients, but whether patients have better outcomes with surgery remains uncertain. Hard pragmatic clinical primary outcome measures are necessary to guide surgical care.
Research participants may not recall their participation but have a better understanding of alternative management options than patients in routine care
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Patient understanding of care interventions, of the clinical uncertainty, and of their participation in clinical research is often poor. We hypothesized that compared to routine care, patients would better understand the prevailing uncertainty when they participated in research.
A questionnaire was administered to patients at the time they attended a follow-up neurovascular clinic 4 to 52 weeks after a care episode where they did or did not participate in a clinical trial. Patients were not reminded whether they had previously participated in a clinical trial. Questions concerned their understanding of the risks/benefits of interventions, the availability of alternative options, whether their personal opinion was taken into consideration, the reason for the final decision, their confidence at having received the best management, and whether they had been research participants.
Between June 2019 and June 2020, 167 patients were recruited; 71 had truly been research participants, while 96 had not. A greater proportion of research patients were aware of the existence of management alternatives (65% versus 44%; P = 0.008). Patients of both groups believed their personal opinion counted in the final decision (76% versus 70%), and patients were equally confident that they had received the best management (94%). Research patients believed they had participated in research 46% of the time, compared to 12% of routine care patients (P = 0.003).
Many patients do not recall that they participated in a clinical trial, but they have a better understanding of the clinical uncertainty and of the availability of alternative management options.
Recruitment in a Pragmatic Randomized Trial on the Management of Unruptured Intracranial Aneurysms
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Citation Excerpt :
CAM is an all-inclusive study that combines pragmatic randomized trials and registries of surgical, endovascular, and conservative management options. The protocol has previously been published.12 Adult patients with at least one unruptured intradural saccular aneurysm are eligible to participate.
The Comprehensive Aneurysm Management (CAM) study is a pragmatic trial designed to manage unruptured intracranial aneurysm (UIA) patients within a care research framework.
CAM is an all-inclusive study. Management options are allocated according to an algorithm combining pre-randomization and clinical judgment. Eligible patients are offered 1:1 randomized allocation of intervention versus conservative management and 1:1 randomization allocation of surgical versus endovascular treatment. Ineligible patients are registered. The primary outcome is survival without dependency (modified Rankin Scale score <3) at 10 years. All UIA patients at 1 center are reported.
Between February 2020 and July 2021, 403 UIA patients were recruited: 179 (44%) in one of the randomized controlled trials (RCTs) and 224 (56%) in one of the registries. Conservative management was recommended for 205 of 403 patients (51%); of 198 (49%) patients considered for curative treatment, 159 (80%) were randomly allocated conservative (n = 81) or curative treatment (n = 78). These patients were younger and had larger aneurysms than those in the observation registry (P = 0.004). In 39 of 198 patients (20%), conservative management was not considered reasonable (17 patients were recommended endovascular, 2 surgery, and 20 the RCT comparing endovascular with surgical treatment). In total, 70 patients were recruited in the RCT comparing surgery and endovascular treatment. After informed discussion at time of consent, 141 of 159 patients (89%) agreed with the randomly allocated management plan, while 11% crossed over to the alternative management option.
CAM was successfully integrated into routine practice. Meaningful conclusions can be obtained if multiple centers actively participate in the trial.
Middle Cerebral Artery Aneurysm Trial (MCAAT): A Randomized Care Trial Comparing Surgical and Endovascular Management of MCA Aneurysm Patients
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There is evidence from ISAT that coiling improves outcomes for many ruptured aneurysms, but this may not be the case for MCA aneurysms.1,11,17 The fundamental question of whether or not unruptured aneurysms should be treated at all will not be addressed by this trial.26,27 An interim examination of the unruptured MCA aneurysm patients included in the CURES trial showed that coiling led to a statistically significantly higher incidence of treatment failure (13 of 48 [27%; 95% CI: 0.17–0.41] compared with 3 of 42 [7%; 95% CI: 0.02–0.19] for clipping, P = 0.025).1
Whether the best management of middle cerebral artery (MCA) aneurysm patients is surgical or endovascular remains uncertain, with little evidence to guide decision-making. A randomized care trial offering MCA aneurysm patients a 50% chance of surgical and a 50% chance of endovascular management may optimize outcomes in the presence of uncertainty.
The Middle Cerebral Artery Aneurysm Trial (MCAAT) is an investigator-initiated, multicenter, parallel group, prospective, 1:1 randomized controlled clinical trial. All adult patients with MCA aneurysms, ruptured or unruptured, amenable to surgical and endovascular treatment can be included. The composite primary outcome is “Treatment Success”: (i) occlusion or exclusion of the aneurysm using the allocated treatment modality; (ii) no intracranial hemorrhage during follow-up; (iii) no retreatment of the target aneurysm during follow-up, (iv) no residual aneurysm on angiographic follow-up; and (v) independence (mRS <3) at 1 year. The trial tests 2 versions of the same hypothesis (one for ruptured and one for unruptured MCA aneurysm patients): Surgical management will lead to a 15% absolute increase in the proportion of patients reaching Treatment Success from 55% to 70% (ruptured) or from 75% to 90% (unruptured aneurysm patients) compared with endovascular treatment (any method). In this pragmatic trial, outcome evaluations are by treating physicians, except for 1-year angiographic results which will be core lab assessed. The trial will be monitored by an independent data safety monitoring committee to assure safety of participants. MCAAT is registered at clinicaltrials.gov: NCT05161377.
Patients with MCA aneurysms can be optimally managed within a care trial protocol.
Unruptured aneurysms: Why observational studies fall short no matter how “Big” the Data
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Citation Excerpt :
A true science of practice regarding the management of UIA patients is possible. The Comprehensive Aneurysm Management (CAM) trial has been designed as a care trial, combining clinical care and research in the best medical interest of the patient [3]. Although its general objective is ambitious, we see no other way to finally practice outcome-based medical care.
The best management of unruptured intracranial aneurysms (UIAs) remains unknown, despite multiple observational studies. A randomized trial (RCT) is in order. Yet, a National Institute Neurological Disorders and Stroke workshop has once again proposed to use prospective observational studies (POS) of large databases to address such problems.
We review the historical misconceptions that have been associated with observations of UIAs and their treatments. We critically examine some recent methods that have been proposed to address shortcomings of observational studies. We finally review the ethical principles underlying the use of trial methods in the care of patients.
Replacing RCTs with POS submits patients to management options that have never been proven beneficial, while making them involuntary research subjects of studies that are inevitably biased. A science of practice cannot be an outsider's examination of the behavior of clinicians incapable of questioning their practice. The thesis we propose is that a science of practice must not only eventually determine what best practice will be; It must engage agents involved in medical practice to transparently reveal the uncertainty that calls for management options to be offered under the guidance of declared and controlled care research, to optimize patient outcomes in spite of the uncertainty.
To use POS rather than RCTs in medical practice is to renege on scientific and ethical principles that characterize modern medicine. Instead, we must learn to integrate care research into our practice to provide optimal medical care in real time.
Experience using pragmatic care trials to guide neurovascular practice under uncertainty
2020, Neurochirurgie
Citation Excerpt :
Finally, the ethical and scientific concepts, as well as the practical results that we believe can justify the care trial approach will be discussed. Nine care trials are now available to help clinicians provide outcome-based neurovascular care in real-time [5,6,25–31] The various care trials, registration numbers, number of patients enrolled in each trial, and corresponding publications are summarized in Table 1. As of March 10, 2020 a total of 1212 neurovascular patients have thus far been recruited in various care trials in a single center.
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Pragmatic care trials were used to address long standing dilemmas regarding rival management options or to offer innovative treatments for 1212 neurovascular patients recruited in an elective or acute care context. Adopting care trial methodology had an immediate impact on clinical practice, replacing unrepeatable treatment decisions by 1:1 randomized allocation whenever reliable knowledge about best management was not available. The care trial approach transformed unfounded medical practice into verifiable outcome-based medical care and reserved authoritative recommendations for care options that had previously been validated. Criticisms we have encountered include mainly the pragmatic trial design choices, with insufficient selection of patients and clinicians, too-flexible protocols, lack of funding and feasibility.
Care trials can be integrated into neurovascular practice. Although they remain a work in progress, the approach curtails the practice of unverifiable medicine and offers patients optimal care in the presence of uncertainty.

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: Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Original ArticleComprehensive Aneurysm Management (CAM): An All-Inclusive Care Trial for Unruptured Intracranial Aneurysms

Background

Methods

Results

Conclusions

Introduction

Section snippets

Objectives

Methods

Discussion

Conclusion

CRediT authorship contribution statement

Lancet Neurol

Clin Neurol Neurosurg

Lancet Neurol

Lancet

Lancet

J Clin Epidemiol

World Neurosurg

J Neuroradiol

J Clin Epidemiol

Prevalence and risk of rupture of intracranial aneurysms: a systematic review

Stroke

Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis

Stroke

Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis

Stroke

Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture

J Neurosurg

The natural course of unruptured cerebral aneurysms in a Japanese cohort

N Engl J Med

Small unruptured intracranial aneurysm verification study: SUAVe study. Japan

Stroke

Unruptured intracranial aneurysms: a review

J Neurosurg

Volumes, outcomes, and complications after surgical versus endovascular treatment of aneurysms in the United States (1993-2015): continued evolution versus steady-state after more than 2 decades of practice

The Barrow Ruptured Aneurysm Trial

J Neurosurg

The TEAM trial: safety and efficacy of endovascular treatment of unruptured intracranial aneurysms in the prevention of aneurysmal hemorrhages: a randomized comparison with indefinite deferral of treatment in 2002 patients followed for 10 years

Trials

A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials

Trials

Reflections on the TEAM trial: why clinical care and research should be reconciled

Can J Neurol Sci

Treatment of unruptured intracranial aneurysms: a nationwide assessment of effectiveness

AJNR Am J Neuroradiol

Original Article
Comprehensive Aneurysm Management (CAM): An All-Inclusive Care Trial for Unruptured Intracranial Aneurysms