Ethical Problems of Observational Studies and Big Data Compared to Randomized Trials.

The temptation to use prospective observational studies (POS) instead of conducting difficult trials (RCTs) has always existed, but with the advent of powerful computers and large databases, it can become almost irresistible. We examine the potential consequences, were this to occur, by comparing two hypothetical studies of a new treatment: one RCT, and one POS. The POS inevitably submits more patients to inferior research methodology. In RCTs, patients are clearly informed of the research context, and 1:1 randomized allocation between experimental and validated treatment balances risks for each patient. In POS, for each patient, the risks of receiving inferior treatment are impossible to estimate. The research context and the uncertainty are down-played, and patients and clinicians are at risk of becoming passive research subjects in studies performed from an outsider's view, which potentially has extraneous objectives, and is conducted without their explicit, autonomous, and voluntary involvement and consent.

Reliability of study endpoint adjudication in a pragmatic trial on brain arteriovenous malformations.

BACKGROUND: The results of a clinical trial are given in terms of primary and secondary outcomes that are obtained for each patient. Just as an instrument should provide the same result when the same object is measured repeatedly, the agreement of the adjudication of a clinical outcome between various raters is fundamental to interpret study results. The reliability of the adjudication of study endpoints determined by examination of the electronic case report forms of a pragmatic trial has not previously been tested. METHODS: The electronic case report forms of 62/434 (14%) patients selected to be observed in a study on brain AVMs were independently examined twice (4 weeks apart) by 8 raters who judged whether each patient had reached the following study endpoints: (1) new intracranial hemorrhage related to AVM or to treatment; (2) new non-hemorrhagic neurological event; (3) increase in mRS ≥1; (4) serious adverse events (SAE). Inter and intra-rater reliability were assessed using Gwet's AC1 (κG) statistics, and correlations with mRS score using Cramer's V test. RESULTS: There was almost perfect agreement for intracranial hemorrhage (92% agreement; κG = 0.84 (95%CI: 0.76-0.93), and substantial agreement for SAEs (88% agreement; κG = 0.77 (95%CI: 0.67-0.86) and new non-hemorrhagic neurological event (80% agreement; κG = 0.61 (95%CI: 0.50-0.72). Most endpoints correlated (V = 0.21-0.57) with an increase in mRS of ≥1, an endpoint which was itself moderately reliable (76% agreement; κG = 0.54 (95%CI: 0.43-0.64). CONCLUSION: Study endpoints of a pragmatic trial were shown to be reliable. More studies on the reliability of pragmatic trial endpoints are needed.

The use and abuse of survival analysis and Kaplan-Meier curves in surgical trials.

BACKGROUND: Survival analysis based on Cox regression and Kaplan-Meier curves, initially devised for oncology trials, have frequently been used in other contexts where fundamental statistical assumptions (such as a constant hazard ratio) are not satisfied. This is almost always the case in trials that compare surgery with medical management. METHODS: We review a trial that compared extracranial-intracranial bypass surgery (EC-IC bypass) with medical management (MM) of patients with symptomatic occlusion of the carotid or middle cerebral artery, where it was claimed that surgery was of no benefit. We discuss a hypothetical study and review other neurovascular trials which have also used survival analysis to compare results. RESULTS: The trial comparing EC-IC bypass and MM did not satisfy the fundamental proportional hazard assumption necessary for valid analyses. This was also the case for two prior EC-IC bypass trials, as well as for other landmark neurovascular studies, such as the trials comparing endarterectomy with MM for carotid stenoses, or for the trial that compared intervention and MM for unruptured brain arteriovenous malformations. While minor deviations may have little effect on large trials, it may be impossible to show the benefits of surgery when trial size is small and deviations large. CONCLUSION: Survival analyses are inappropriate in RCTs comparing surgery with conservative management, unless survival is calculated after the postoperative period. Alternative ways to compare final clinical outcomes, using for example a fixed follow-up period, should be planned for preventive surgical trials that compare intervention with conservative management.

Endovascular Parent Vessel Occlusion Versus Flow Diversion in the Treatment of Large and Giant Aneurysms: A Randomized Comparison.

OBJECTIVE: Parent vessel occlusion (PVO) is a time-honored treatment for unclippable or uncoilable intracranial aneurysms. Flow diversion (FD) is a recent endovascular alternative that can occlude the aneurysm and spare the parent blood vessel. Our aim was to compare outcomes of FD with endovascular PVO. METHODS: This is a prespecified treatment subgroup analysis of the Flow diversion in Intracranial Aneurysms trial (FIAT). FIAT was an investigator-led parallel-group all-inclusive pragmatic randomized trial. For each patient, clinicians had to prespecify an alternative management option to FD before stratified randomization. We report all patients for whom PVO was selected as the best alternative treatment to FD. The primary outcome was a composite of core-lab determined angiographic occlusion or near-occlusion at 3-12 months combined with an independent clinical outcome (mRS<3). Primary analyses were intent-to-treat. There was no blinding. RESULTS: There were 45 patients (16.2% of the 278 FIAT patients randomized between 2011 and 2020 in 3 centers): 22 were randomly allocated to FD and 23 to PVO. Aneurysms were mainly large or giant (mean 22 mm) anterior circulation (mainly carotid) aneurysms. A poor primary outcome was reached in 11/22 FD (50.0%) compared to 9/23 PVO patients (39.1%) (RR: 1.28, 95% CI [0.66-2.47]; P = 0.466). Morbidity (mRS >2) at 1 year occurred in 4/22 FD and 6/23 PVO patients. Angiographic results and serious adverse events were similar. CONCLUSIONS: The comparison between PVO and FD was inconclusive. More randomized trials are needed to better determine the role of FD in large aneurysms eligible for PVO.

Understanding categories or subgroups and a common clinical reasoning error: the example of aneurysm size and neck width.

BACKGROUND: Individualized clinical decisions are often made by considering some patient or lesion characteristics that are thought to have an impact on the efficacy or safety of treatment. For example, aneurysm size and neck width have often been determinants of treatment choices in neurovascular practice. METHODS: We review observational and randomized data on the influence of aneurysm or neck size on angiographic results of coiling, stent-assisted coiling, or surgical clipping. New RCT data are used to demonstrate the shortcomings of managing patients using clinical judgment regarding patient or lesion characteristics. We discuss why clinical decisions should not be based on comparisons of different patients treated by the same treatment. Clinical decision making requires a comparison between the same patients treated with different treatments in a randomized trial. RESULTS: The results of endovascular treatment of large or wide-necked aneurysms are always inferior to those of small or narrow-necked aneurysms, in observational as well as in randomized studies. However, this fact alone is not sufficient to infer that patients with small aneurysms should be coiled, while those with large aneurysms should be managed with stenting or surgical clipping. The purported superiority of clipping for large aneurysms could not be demonstrated in recent RCTs (while surgery was found superior for small aneurysms). Similarly, the superiority of stent-assisted coiling for wide-necked aneurysms was not shown in another recent RCT. CONCLUSION: Clinical experience and observational studies alone can mislead practice. Proper clinical decisions for individuals requires randomized evidence.

Understanding the role of randomization in clinical research and practice.

BACKGROUND: The scientific role randomization plays in clinical research is universally recognized, but poorly understood. In stark contrast, the ethical role randomization plays in the proper care of patients in the presence of uncertainty has been almost completely ignored. METHODS: We review the introduction of randomization in the design of experiments, its first use in Britain, and its essential role in analysis of statistical results. We also review Thomas Chalmers' argument from 1975 that showed the ethical role randomization can play in the care of patients. We discuss how Chalmers' vision can be generalized to all contexts of clinical uncertainty. DISCUSSION: Randomization is not only essential to the validity of statistical tests, it is also the best way to learn from experience. Although Chalmers' admonition to 'Randomize the first patient' pertained to the use of innovations, the notion that randomized allocation can be done in the best interest of patients is generalizable to all medical or surgical interventions that have yet to be proven beneficial, opening the perspective that care research can be integrated into practice in the best medical interest of patients. CONCLUSION: Randomized allocation plays crucial scientific and ethical roles both in research and practice. It is the most efficient way to learn from experience. Prior to this gain in knowledge, it is the way to optimize care in the presence of uncertainty.

The small trial problem.

BACKGROUND: Many randomized trials that aim to assess new or commonly used medical or surgical interventions have been so small that the validity of conclusions becomes questionable. METHODS: We illustrate the small trial problem using the power calculation of five Cochrane-reviewed studies that compared vertebroplasty versus placebo interventions. We discuss some of the reasons why the statistical admonition not to dichotomize continuous variables may not apply to the calculation of the number of patients required for trials to be meaningful. RESULTS: Placebo-controlled vertebroplasty trials planned to recruit between 23 and 71 patients per group. Four of five studies used the standardized mean difference of a continuous pain variable (centimeters on the visual analog scale (VAS)) to plan implausibly small trials. What is needed is not a mean effect at the population level but a measure of efficacy at the patient level. Clinical practice concerns the care of individual patients that vary in many more respects than the variation around the mean of a single selected variable. The inference from trial to practice concerns the frequency of success of the experimental intervention performed one patient at a time. A comparison of the proportions of patients reaching a certain threshold is a more meaningful method that appropriately requires larger trials. CONCLUSION: Most placebo-controlled vertebroplasty trials used comparisons of means of a continuous variable and were consequently very small. Randomized trials should instead be large enough to account for the diversity of future patients and practices. They should offer an evaluation of a clinically meaningful number of interventions performed in various contexts. Implications of this principle are not specific to placebo-controlled surgical trials. Trials designed to inform practice require a per-patient comparison of outcomes and the size of the trial should be planned accordingly.

Endovascular treatment of brain arteriovenous malformations: clinical outcomes of patients included in the registry of a pragmatic randomized trial.

OBJECTIVE: The role of endovascular treatment in the management of patients with brain arteriovenous malformations (AVMs) remains uncertain. AVM embolization can be offered as stand-alone curative therapy or prior to surgery or stereotactic radiosurgery (SRS) (pre-embolization). The Treatment of Brain AVMs Study (TOBAS) is an all-inclusive pragmatic study that comprises two randomized trials and multiple registries. METHODS: Results from the TOBAS curative and pre-embolization registries are reported. The primary outcome for this report is death or dependency (modified Rankin Scale [mRS] score > 2) at last follow-up. Secondary outcomes include angiographic results, perioperative serious adverse events (SAEs), and permanent treatment-related complications leading to an mRS score > 2. RESULTS: From June 2014 to May 2021, 1010 patients were recruited in TOBAS. Embolization was chosen as the primary curative treatment for 116 patients and pre-embolization prior to surgery or SRS for 92 patients. Clinical and angiographic outcomes were available in 106 (91%) of 116 and 77 (84%) of 92 patients, respectively. In the curative embolization registry, 70% of AVMs were ruptured, and 62% were low-grade AVMs (Spetzler-Martin grade I or II), while the pre-embolization registry had 70% ruptured AVMs and 58% low-grade AVMs. The primary outcome of death or disability (mRS score > 2) occurred in 15 (14%, 95% CI 8%-22%) of the 106 patients in the curative embolization registry (4 [12%, 95% CI 5%-28%] of 32 unruptured AVMs and 11 [15%, 95% CI 8%-25%] of 74 ruptured AVMs) and 9 (12%, 95% CI 6%-21%) of the 77 patients in the pre-embolization registry (4 [17%, 95% CI 7%-37%] of 23 unruptured AVMs and 5 [9%, 95% CI 4%-20%] of 54 ruptured AVMs) at 2 years. Embolization alone was confirmed to occlude the AVM in 32 (30%, 95% CI 21%-40%) of the 106 curative attempts and in 9 (12%, 95% CI 6%-21%) of 77 patients in the pre-embolization registry. SAEs occurred in 28 of the 106 attempted curative patients (26%, 95% CI 18%-35%, including 21 new symptomatic hemorrhages [20%, 95% CI 13%-29%]). Five of the new hemorrhages were in previously unruptured AVMs (n = 32; 16%, 95% CI 5%-33%). Of the 77 pre-embolization patients, 18 had SAEs (23%, 95% CI 15%-34%), including 12 new symptomatic hemorrhages [16%, 95% CI 9%-26%]). Three of the hemorrhages were in previously unruptured AVMs (3/23; 13%, 95% CI 3%-34%). CONCLUSIONS: Embolization as a curative treatment for brain AVMs was often incomplete. Hemorrhagic complications were frequent, even when the specified intent was pre-embolization before surgery or SRS. Because the role of endovascular treatment remains uncertain, it should preferably, when possible, be offered in the context of a randomized trial.

Patient Selection in a Pragmatic Study on the Management of Patients with Brain Arteriovenous Malformations.

BACKGROUND: The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is an all-inclusive pragmatic study comprising 2 randomized clinical trials (RCTs). Patients excluded from the RCTs are followed in parallel treatment and observation registries, allowing a comparison between RCT and registry patients. METHODS: The first randomized clinical trial (RCT-1) offers 1:1 randomized allocation of intervention versus conservative management for patients with arteriovenous malformation (AVM). The second randomized clinical trial (RCT-2) allocates 1:1 pre-embolization or no pre-embolization to surgery or radiosurgery patients judged treatable with or without embolization. Characteristics of RCT patients are reported and compared to registry patients. RESULTS: From June 2014 to May 2021, 1010 patients with AVM were recruited; 498 patients were observed and 373 were included in the treatment registries. Randomized allocation in RCT-1 was applied to 139 (26%) of the 512 patients (including 127 of 222 [57%] with unruptured AVMs) considered for curative treatment. RCT-1 AVM patients differed (in rupture status, Spetzler-Martin grade and baseline modified Rankin Score) from those in the observation or treatment registries (P < 0.001). Most patients had small (<3 cm; 71%) low-grade (Spetzler-Martin I-II; 64%) unruptured (91%) AVMs. The allocated management was conservative (n = 71) or curative (n = 68), using surgery (n = 39), embolization (n = 16), or stereotactic radiosurgery (n = 13). Pre-embolization was considered for 179/309 (58%) patients allocated/assigned to surgery or stereotactic radiosurgery; 87/179 (49%) were included in RCT-2. RCT-2 patient AVMs differed in size, eloquence and grade from patients of the pre-embolization registry (P < 0.01). Most had small (<3 cm in 82%) low-grade (83%) AVMs in non-eloquent brain (64%). CONCLUSIONS: Patients included in the RCTs differ significantly from registry patients. Meaningful results can be obtained if multiple centers actively participate in the TOBAS RCTs.

Surgical treatment of brain arteriovenous malformations: clinical outcomes of patients included in the registry of a pragmatic randomized trial.

OBJECTIVE: The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is a pragmatic study that includes 2 randomized trials and registries of treated or conservatively managed patients. The authors report the results of the surgical registry. METHODS: TOBAS patients are managed according to an algorithm that combines clinical judgment and randomized allocation. For patients considered for curative treatment, clinicians selected from surgery, endovascular therapy, or radiation therapy as the primary curative method, and whether observation was a reasonable alternative. When surgery was selected and observation was deemed unreasonable, the patient was not included in the randomized controlled trial but placed in the surgical registry. The primary outcome of the trial was mRS score > 2 at 10 years (at last follow-up for the current report). Secondary outcomes include angiographic results, perioperative serious adverse events, and permanent treatment-related complications leading to mRS score > 2. RESULTS: From June 2014 to May 2021, 1010 patients were recruited at 30 TOBAS centers. Surgery was selected for 229/512 patients (44%) considered for curative treatment; 77 (34%) were included in the surgery versus observation randomized trial and 152 (66%) were placed in the surgical registry. Surgical registry patients had 124/152 (82%) ruptured and 28/152 (18%) unruptured arteriovenous malformations (AVMs), with the majority categorized as low-grade Spetzler-Martin grade I-II AVM (118/152 [78%]). Thirteen patients were excluded, leaving 139 patients for analysis. Embolization was performed prior to surgery in 78/139 (56%) patients. Surgical angiographic cure was obtained in 123/139 all-grade (89%, 95% CI 82%-93%) and 105/110 low-grade (95%, 95% CI 90%-98%) AVM patients. At the mean follow-up of 18.1 months, 16 patients (12%, 95% CI 7%-18%) had reached the primary safety outcome of mRS score > 2, including 11/16 who had a baseline mRS score ≥ 3 due to previous AVM rupture. Serious adverse events occurred in 29 patients (21%, 95% CI 15%-28%). Permanent treatment-related complications leading to mRS score > 2 occurred in 6/139 patients (4%, 95% CI 2%-9%), 5 (83%) of whom had complications due to preoperative embolization. CONCLUSIONS: The surgical treatment of brain AVMs in the TOBAS registry was curative in 88% of patients. The participation of more patients, surgeons, and centers in randomized trials is needed to definitively establish the role of surgery in the treatment of unruptured brain AVMs. Clinical trial registration no.: NCT02098252 (ClinicalTrials.gov).

Recruitment in a Pragmatic Randomized Trial on the Management of Unruptured Intracranial Aneurysms.

OBJECTIVES: The Comprehensive Aneurysm Management (CAM) study is a pragmatic trial designed to manage unruptured intracranial aneurysm (UIA) patients within a care research framework. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

BACKGROUND: 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. METHODS: 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. CONCLUSIONS: Patients with MCA aneurysms can be optimally managed within a care trial protocol.

Clinical Uncertainty and Equipoise in the Management of Recurrent Glioblastoma.

BACKGROUND: A significant proportion of glioblastoma (GBM) patients are considered for repeat resection, but evidence regarding best management remains elusive. Our aim was to measure the degree of clinical uncertainty regarding reoperation for patients with recurrent GBM. METHODS: We first performed a systematic review of agreement studies examining the question of repeat resection for recurrent GBM. An electronic portfolio of 37 pathologically confirmed recurrent GBM patients including pertinent magnetic resonance images and clinical information was assembled. To measure clinical uncertainty, 26 neurosurgeons from various countries, training backgrounds, and years' experience were asked to select best management (repeat surgery, other nonsurgical management, or conservative), confidence in recommended management, and whether they would include the patient in a randomized trial comparing surgery with nonsurgical options. Agreement was evaluated using κ statistics. RESULTS: The literature review did not reveal previous agreement studies examining the question. In our study, agreement regarding best management of recurrent GBM was slight, even when management options were dichotomized (repeat surgery vs. other options; κ=0.198 [95% confidence interval: 0.133-0.276]). Country of practice, years' experience, and training background did not change results. Disagreement and clinical uncertainty were more pronounced within clinicians with (κ=0.167 [0.055-0.314]) than clinicians without neuro-oncology fellowship training (κ=0.601 [0.556-0.646]). A majority (51%) of responders were willing to include the patient in a randomized trial comparing repeat surgery with nonsurgical alternatives in 26/37 (69%) of cases. CONCLUSION: There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with recurrent glioblastoma to support the need for a randomized controlled trial.

Angiographic results of surgical or endovascular treatment of intracranial aneurysms: a systematic review and inter-observer reliability study.

PURPOSE: Results of surgical or endovascular treatment of intracranial aneurysms are often assessed using angiography. A reliable method to report results irrespective of treatment modality is needed to enable comparisons. Our goals were to systematically review existing classification systems, and to propose a 3-point classification applicable to both treatments and assess its reliability. METHODS: We conducted two systematic reviews on classification systems of angiographic results after clipping or coiling to select a simple 3-category scale that could apply to both treatments. We then circulated an electronic portfolio of angiograms of clipped (n=30) or coiled (n=30) aneurysms, and asked raters to evaluate the degree of occlusion using this scale. Raters were also asked to choose an appropriate follow-up management for each patient based on the degree of occlusion. Agreement was assessed using Krippendorff's α statistics (αK), and relationship between occlusion grade and clinical management was analyzed using Fisher's exact and Cramer's V tests. RESULTS: The systematic reviews found 70 different grading scales with heterogeneous reliability (kappa values from 0.12 to 1.00). The 60-patient portfolio was independently evaluated by 19 raters of diverse backgrounds (neurosurgery, radiology, and neurology) and experience. There was substantial agreement (αK=0.76, 95%CI, 0.67-0.83) between raters, regardless of background, experience, or treatment used. Intra-rater agreement ranged from moderate to almost perfect. A strong relationship was found between angiographic grades and management decisions (Cramer's V: 0.80±0.12). CONCLUSION: A simple 3-point scale demonstrated sufficient reliability to be used in reporting aneurysm treatments or in evaluating treatment results in comparative randomized trials.

Surgical or Endovascular Management of Middle Cerebral Artery Aneurysms: A Randomized Comparison.

OBJECTIVE: There are few randomized data comparing clipping and coiling for middle cerebral artery (MCA) aneurysms. We analyzed results from patients with MCA aneurysms enrolled in the CURES (Collaborative UnRuptured Endovascular vs. Surgery) and ISAT-2 (International Subarachnoid Aneurysm Trial II) randomized trials. METHODS: Both trials are investigator-led parallel-group 1:1 randomized studies. CURES includes patients with 3-mm to 25-mm unruptured intracranial aneurysms (UIAs), and ISAT-2 includes patients with ruptured aneurysms (RA) for whom uncertainty remains after ISAT. The primary outcome measure of CURES is treatment failure: 1) failure to treat the aneurysm, 2) intracranial hemorrhage during follow-up, or 3) residual aneurysm at 1 year. The primary outcome of ISAT-2 is death or dependency (modified Rankin Scale score >2) at 1 year. One-year angiographic outcomes are systematically recorded. RESULTS: There were 100 unruptured and 71 ruptured MCA aneurysms. In CURES, 90 patients with UIA have been treated and 10 await treatment. Surgical and endovascular management of unruptured MCA aneurysms led to treatment failure in 3/42 (7%; 95% confidence interval [CI], 0.02-0.19) for clipping and 13/48 (27%; 95% CI, 0.17-0.41) for coiling (P = 0.025). All 71 patients with RA have been treated. In ISAT-2, patients with ruptured MCA aneurysms managed surgically had died or were dependent (modified Rankin Scale score >2) in 7/38 (18%; 95% CI, 0.09-0.33) cases, and 8/33 (24%; 95% CI, 0.13-0.41) for endovascular. One-year imaging results were available in 80 patients with UIA and 62 with RA. Complete aneurysm occlusion was found in 30/40 (75%; 95% CI, 0.60-0.86) patients with UIA allocated clipping, and 14/40 (35%; 95% CI, 0.22-0.50) patients with UIA allocated coiling. Complete aneurysm occlusion was found in 24/34 (71%; 95% CI, 0.54-0.83) patients with RA allocated clipping, and 15/28 (54%; 95% CI, 0.36-0.70) patients with RA allocated coiling. CONCLUSIONS: Randomized data from 2 trials show that better efficacy may be obtained with surgical management of patients with MCA aneurysms.

Ethical care requires pragmatic care research to guide medical practice under uncertainty.

BACKGROUND: The current research-care separation was introduced to protect patients from explanatory studies designed to gain knowledge for future patients. Care trials are all-inclusive pragmatic trials integrated into medical practice, with no extra tests, risks, or cost, and have been designed to guide practice under uncertainty in the best medical interest of the patient. PROPOSED REVISION: Patients need a distinction between validated care, previously verified to provide better outcomes, and promising but unvalidated care, which may include unnecessary or even harmful interventions. While validated care can be practiced normally, unvalidated care should only be offered within declared pragmatic care research, designed to protect patients from harm. The validated/unvalidated care distinction is normative, necessary to the ethics of medical practice. Care trials, which mark the distinction and allow the tentative use of promising interventions necessarily involve patients, and thus the design and conduct of pragmatic care research must respect the overarching rule of care ethics "to always act in the best medical interest of the patient." Yet, unvalidated interventions offered in contexts of medical uncertainty cannot be prescribed or practiced as if they were validated care. The medical interests of current patients are best protected when unvalidated practices are restricted to a care trial protocol, with 1:1 random allocation (or "hemi-prescription") versus previously validated care, to optimize potential benefits and minimize risks for each patient. CONCLUSION: Pragmatic trials can regulate medical practice by providing (i) a transparent demarcation between unvalidated and validated care; (ii) norms of medical conduct when using tests and interventions of yet unknown benefits in practice; and eventually (iii) a verdict regarding optimal care.

Practicing outcome-based medical care using pragmatic care trials.

The current separation between medical research and care is an obstacle to essential aspects of good medical practice: the verification that care interventions actually deliver the good outcomes they promise, and the use of scientific methods to optimize care under uncertainty. Pragmatic care trials have been designed to address these problems. Care trials are all-inclusive randomized trials integrated into care. Every item of trial design is selected in the best medical interest of participating patients. Care trials can eventually show what constitutes good medical practice based on patient outcomes. In the meantime, care trials give clinicians and patients the scientific methods necessary for optimization of medical care when no one really knows what to do.We report the progress of 9 randomized care trials that were used to guide the endovascular or surgical management of 1212 patients with acute stroke, intracranial aneurysms, and arteriovenous malformations in a single center in an elective or acute care context. Care trials were used to address long-standing dilemmas regarding rival medical, surgical, or endovascular management options or to offer innovative instead of standard treatments. The trial methodology, by replacing unrepeatable treatment decisions by 1:1 randomized allocation whenever reliable knowledge was not available, had an immediate impact, transforming unverifiable dogmatic medical practice into verifiable outcome-based medical care. We believe the approach is applicable to all medical or surgical domains, but widespread adoption may require the revision of many currently prevalent views regarding the role of research in clinical practice.