D. Roy

Analysis by Categorizing or Dichotomizing Continuous Variables Is Inadvisable: An Example from the Natural History of Unruptured Aneurysms

SUMMARY: In medical research analyses, continuous variables are often converted into categoric variables by grouping values into ≥2 categories. The simplicity achieved by creating ≥2 artificial groups has a cost: Grouping may create rather than avoid problems. In particular, dichotomization leads to a considerable loss of power and incomplete correction for confounding factors. The use of data-derived “optimal” cut-points can lead to serious bias and should at least be tested on independent observations to assess their validity. Both problems are illustrated by the way the results of a registry on unruptured intracranial aneurysms are commonly used. Extreme caution should restrict the application of such results to clinical decision-making. Categorization of continuous data, especially dichotomization, is unnecessary for statistical analysis. Continuous explanatory variables should be left alone in statistical models.

Flow Diversion in Aneurysms Trial: the Design of the FIAT study

Intracranial aneurysms, particularly large and giant, fusiform or recurrent aneurysms are increasingly treated with flow diverters (FDs), a recently introduced and approved neurovascular device. While some rare cases may not be treated any other way, in most patients a more conventional, conservative, or validated approach such as coiling, parent vessel occlusion, or surgical clipping exists. Only a randomized clinical trial can answer the question of which treatment option leads to better patient outcomes. We report the design of the FIAT study, a clinical care trial aiming to compare angiographic and clinical outcomes following treatment with a Flow-Diverter or with the best conventional treatment option. The FIAT study will include both a randomized and a registry portion. Patients will be proposed randomization to either FD stenting or best conventional treatment option (observation, coiling, stenting, or clipping) as determined by the treating physician. FIAT will recruit a total of 338 patients, to show that i) FD stenting can be performed with an ‘acceptable’ immediate complication rate of less than 15% morbidity and mortality (defined as mRS > 2); ii) FD stenting can increase from 75 to 90% the proportion of patients with a “good outcome”, defined as complete or near-complete occlusion of the aneurysm AND a good clinical outcome (mRS ≤ 2) at one year, as compared to the best conventional option. The FIAT study provides a scientific and ethical context to care for patients eligible for flow-diversion therapy.

Liquid embolization material reduces the delivered radiation dose: clinical myth or reality?

BACKGROUND AND PURPOSE: To be radiopaque, BAVM embolization products must contain high-atomic-number materials, which may also attenuate photon beams delivered with radiosurgery. This “shielding effect” has been invoked to explain why radiation therapy may be less effective for previously embolized BAVMs. To evaluate the impact of embolization material on radiation dose, we measured and compared the dose delivered to the center of an AVM model, before and following embolization with various materials in a LINAC. MATERIALS AND METHODS: Two in vitro AVM models were constructed by drilling interconnected tubular perforations in plastic water phantoms to simulate nidal vessels. Phantoms were designed to allow the positioning of a radiation detector at their center. One model was embolized with Onyx 18 and a second model, with a combination of Indermil, Lipiodol, tungsten powder, and Onyx 18. The radiation delivered was compared between embolized and nonembolized controls following irradiation with a standard 250-cGy dose. RESULTS: The mean dose of radiation delivered to the model embolized with Onyx alone was 244 ± 5 cGy before and 246 ± 5 cGy following embolization. The mean dose of radiation delivered to the model embolized with various agents was 242 ± 5 cGy before, and 254 ± 5 cGy after embolization. CONCLUSIONS: Embolic material did not reduce the radiation dose delivered by a LINAC to the center of our experimental BAVM models. The shielding effect may be compensated by scattered and reflected radiation.

Embolization as One Modality in a Combined Strategy for the Management of Cerebral Arteriovenous Malformations

We attempted to assess clinical results of management of cerebral arteriovenous malformation using a combination of endovascular, surgical and radiotherapeutic approaches. We retrospectively reviewed the angiographic and clinical data on prospectively collected consecutive patients treated by embolization from 1994 to 2004. The general philosophy was to attempt treatment by a combination of approaches only when an angiographic cure was likely or at least possible. The clinical outcome was assessed according to the modified Rankin scale. Although 404 patients were collected, complete files and follow-ups are available for 227 or 56% only. Most patients presented with hemorrhages (53%) or seizures (23%). The final management consisted in embolization alone in 34%, embolization followed by surgery in 47%, embolization and radiotherapy in 16%, and embolization, surgery and radiotherapy in 3% of patients. The embolization procedure itself could lead to an angiographic cure in only 16% of patients. When the management strategy could be completed, the cure rate increased to 66%. Complications of embolization occurred in 22.6% of patients. Overall clinical outcome was excellent (Rankin 0) in 43%, good (Rankin 1) in 38%, fair (Rankin 2) in 10%, poor (Rankin 3–5) in 2%, and the death rate was 7%. A combined strategy initially designed to provide angiographic cures cannot be completed in a significant number of patients; the total morbidity of treatment remains significant. There is no scientific evidence that cerebral arteriovenous malformations should be treated, and no clinical trial to prove that one approach is better than the other. Various treatment protocols have been proposed on empirical grounds. Small lesions can often be eradicated, with surgery when lesions are superficial, or with radiation therapy for deeper ones. There has been little controversy regarding therapeutic indications in these patients. The management of larger AVMs, sometimes in more eloquent locations, is much more difficult and controversial. Endovascular approaches have initially been developed to meet this challenge. It became quickly evident that embolization alone would rarely suffice to completely cure these lesions. The philosophy behind combined approaches is founded on 2 opinions: 1) There is no proven value of partial embolization, not even “partial benefits”, and treatment should aim at an angiographic cure and 2) By appropriately tailoring all available tools to each situation, such a cure could be reached with minimum or reasonable risks. We have used such a combined strategy for more than a decade now. Endovascular techniques and materials have evolved, and it is perhaps possible today to reach a cure by embolization alone in a larger proportion of patients than before. Aggressive embolizations, aiming for an endovascular cure, even sometimes in large lesions, have recently been promoted for their power or criticized for their risks. But before evaluating the advantages and inconveniences of new treatments, it may be wise to review the results we could achieve with a conventional approach combining endovascular, surgical and radiotherapeutic techniques.

Patients prone to recurrence after endovascular treatment: periprocedural results of the PRET randomized trial on large and recurrent aneurysms.

BACKGROUND AND PURPOSE: Some patients with large or recurrent aneurysms may be at increased risk of recurrence postcoiling. The Patients Prone to Recurrence after Endovascular Treatment (PRET) trial was designed to assess whether hydrogel coils were superior to platinum coils in these high-risk patients. This article reports periprocedural safety and operator-assessed angiographic results from the PRET trial. MATERIALS AND METHODS: PRET was a pragmatic, multicenter, randomized controlled trial. Patients had ≥10-mm aneurysms (PRET-1) or a major recurrence after coiling of an aneurysm of any size (PRET-2). Patients were randomly allocated to hydrogel or control arms (any platinum coil) by using concealed allocation with minimization. Assist devices could be used as clinically required. Aneurysms could be unruptured or recently ruptured. Analyses were on an intent-to-treat basis. RESULTS: Four hundred forty-seven patients were recruited (250 PRET-1; 197 PRET-2). Aneurysms were recently ruptured in 29% of PRET-1 and 4% of PRET-2 patients. Aneurysms were ≥10 mm in all PRET-1 and in 50% of PRET-2 patients. They were wide-neck (≥4 mm) in 70% and in the posterior circulation in 24% of patients. Stents were used in 28% of patients (35% in PRET-2). Coiling was successful in 98%. Adverse events occurred in 28 patients with hydrogel and 23 with platinum coils. Mortality (n = 2, unrelated to treatment) and morbidity (defined as mRS >2 at 1 month) occurred in 25 patients (5.6%; 12 hydrogel, 13 platinum), related to treatment in 10 (4 hydrogel; 6 platinum) (or 2.3% of 444 treated patients). No difference was seen between hydrogel and platinum for any of the indices used to assess safety up to at least 30 days after treatment. At 1 month, 95% of patients were home with a good outcome (mRS ≤2 or unchanged). Operator-assessed angiographic outcomes were satisfactory (complete occlusion or residual neck) in 339 of 447 or 76.4% of patients, with no significant difference between groups. CONCLUSIONS: Endovascular treatment of large and recurrent aneurysms can be performed safely with platinum or hydrogel coils.

Iatrogenic Arterial Perforation during Acute Stroke Interventions

SUMMARY: Arterial perforation is a feared complication of acute stroke intervention. A high index of suspicion is important to recognize this complication and tailor patient management to prevent further deterioration in clinical outcome. This report describes the endovascular management of microcatheter arterial perforation in a 66-year-old woman with an acute left middle cerebral artery stroke. The microcatheter was retained in the patient to seal the perforated site, resulting in good outcome at 3-month follow-up.

A randomized trial on the safety and efficacy of endovascular treatment of unruptured intracranial aneurysms is feasible.

The safety and efficacy of endovascular treatment of unruptured intracranial aneurysms remain undetermined. A randomized trial may be the best way to demonstrate the potential benefits of endovascular management. We propose a randomized, prospective, controlled trial comparing the incidence of subarachnoid haemorrage of patients treated by endovascular coiling as compared to conservative management. We would also study a composite outcome combining SAH and the morbidity of treatment. All patients with one or more unruptured aneurysm >> 3 mm eligible for endovascular treatment would be proposed to participate. The study would be conducted in 40–50 centres. The entire study would enrol 1800 patients, recruited over three years and followed for five years, but would be preceded by a feasibility study on 200 patients. A randomized trial comparing endovascular and conservative treatment could have an important impact on the clinical management of intracranial aneurysms

Uncertainty and Agreement Regarding the Role of Flow Diversion in the Management of Difficult Aneurysms

BACKGROUND AND PURPOSE: The role of flow diversion in the management of aneurysms remains unknown. We sought to evaluate the community agreement regarding indications for flow diversion. MATERIALS AND METHODS: A portfolio of 35 difficult aneurysm cases was sent to 40 clinicians with varying backgrounds and experience. Responders were asked whether they considered flow diversion a treatment option, whether other options were possible, whether recruitment in a randomized trial would be considered, and to select their final choice. Agreement was studied by using κ statistics. RESULTS: Decisions for flow diversion were more frequent (n = 300, 39%) than decisions to coil (n = 163, 21.2%), to observe (n = 121, 15.7%), to occlude the parent vessel (n = 102, 13.2%), or to clip (n = 66, 8.6%). Sidewall aneurysm morphology was associated with flow diversion as the final choice (P = .001). Interjudge agreement was fair at best (κ <0.3) for all cases and all judges, despite high certainty levels (range, 7.2–8.9 ± 2.0 on a 0–10 scale). Agreement was no better within specialties or with more experience. All patients were judged to have other treatment options. Judges were willing to offer trial participation in 417 of 741 (56.3%) scenarios, more frequently when the aneurysm was sidewall (P = .001) or in the anterior circulation (P = .028). CONCLUSIONS: Individuals did not agree regarding the indications for flow diversion. There is sufficient uncertainty to justify trials designed to protect patients from the potential risks of premature adoption of an innovation.

Vertebral artery stump syndrome

After occlusion of flow in an artery, further ischaemic episodes are not expected due to lack of a flow conduit to carry the embolus. In the carotid stump syndrome, ongoing ischaemic events may continue due to collateral flow via the external carotid artery. We report two patients presenting with posterior circulation strokes after documented vertebral artery occlusion, due to a vertebral stump syndrome. Their presentation, the pathophysiology of cervico-vertebral anastomoses and management are described.

Hydrogel versus Bare Platinum Coils in Patients with Large or Recurrent Aneurysms Prone to Recurrence after Endovascular Treatment: A Randomized Controlled Trial

This Level 1 expedited report was a pragmatic, multicenter, parallel, randomized (1:1) trial evaluating patients who were at high risk of aneurysm recurrence after endovascular treatment, including patients with large aneurysms (Patients Prone to Recurrence After Endovascular Treatment PRET-1) or with aneurysms that had previously recurred after coiling (PRET-2). The trial was stopped once 250 patients in PRET-1 and 197 in PRET-2 had been recruited because of slow accrual. A poor primary outcome occurred in 44.4% of those in PRET-1 allocated to platinum compared with 52.5% of patients allocated to hydrogel and in 49.0% in PRET-2 allocated to platinum compared with 42.1% allocated to hydrogel. Adverse events and morbidity were similar. The authors conclude that coiling of large and recurrent aneurysms is safe but often poorly effective according to angiographic results. Hydrogel coiling was not shown to be better than platinum. BACKGROUND AND PURPOSE: Some patients are at high risk of aneurysm recurrence after endovascular treatment: patients with large aneurysms (Patients Prone to Recurrence After Endovascular Treatment PRET-1) or with aneurysms that have previously recurred after coiling (PRET-2). We aimed to establish whether the use of hydrogel coils improved efficacy outcomes compared with bare platinum coils. MATERIALS AND METHODS: PRET was an investigator-led, pragmatic, multicenter, parallel, randomized (1:1) trial. Randomized allocation was performed separately for patients in PRET-1 and PRET-2, by using a Web-based platform ensuring concealed allocation. The primary outcome was a composite of a residual/recurrent aneurysm, adjudicated by a blinded core laboratory, or retreatment, intracranial bleeding, or mass effect during the 18-month follow-up. Secondary outcomes included adverse events, mortality, and morbidity (mRS > 2). The hypothesis was that hydrogel would decrease the primary outcome from 50% to 30% at 18 months, necessitating 125 patients per group (500 for PRET-1 and PRET-2). RESULTS: The trial was stopped once 250 patients in PRET-1 and 197 in PRET-2 had been recruited because of slow accrual. A poor primary outcome occurred in 44.4% (95% CI, 35.5%–53.2%) of those in PRET-1 allocated to platinum compared with 52.5% (95% CI, 43.4%–61.6%) of patients allocated to hydrogel (OR, 1.387; 95% CI, 0.838–2.295; P = .20) and in 49.0% (95% CI, 38.8%–59.1%) in PRET-2 allocated to platinum compared with 42.1% (95% CI, 32.0%–52.2%) allocated to hydrogel (OR, 0.959; 95% CI, 0.428–1.342; P = .34). Adverse events and morbidity were similar. There were 3.6% deaths (1.4% platinum, 5.9% hydrogel; P = .011). CONCLUSIONS: Coiling of large and recurrent aneurysms is safe but often poorly effective according to angiographic results. Hydrogel coiling was not shown to be better than platinum.