Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and endpoint definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on pre-defined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using NIH/NINDS common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability.¹ In the U.S., aSAH more often affects women and underrepresented minority groups than ischemic stroke or intracerebral hemorrhage.² With advances in neurosurgical, neurointerventional, and neurocritical care, functional outcomes after aSAH have improved over time, but half of survivors remain disabled.³ Although management approaches have changed substantially over time, relatively few aSAH treatments have been rigorously tested in randomized clinical trials (RCTs).^4–11 In contrast to the American Heart Association’s ischemic stroke guidelines, which provide >60 recommendations based on high-quality RCT data, the aSAH guidelines provide only a handful, noting that “large, multicenter, randomized trial data confirming effectiveness are usually lacking for many of the interventions discussed.”^12–14

The paucity of RCTs in aSAH does not result from a lack of ideas to test. Numerous interventions have been studied in preclinical models and observational studies and appear to have promise for improving functional outcomes in aSAH patients.¹⁵ Meanwhile, clinical practice has evolved in different directions among high-volume centers, resulting in high practice variability,¹⁶ and optimal approaches remain uncertain. As aSAH is a relatively rare form of stroke, enrollment of large patient samples is challenging and RCTs cannot keep up with the evolution of clinical practice. A key barrier to rigorously testing interventions and comparing current practice approaches is the lack of efficient infrastructure to facilitate multicenter, multidisciplinary collaboration on high-quality pragmatic RCTs in a complex disease.¹⁵ Existing trial networks such as NIH/NINDS StrokeNet offer outstanding opportunities for standing up individual trials, but do not currently serve as an aSAH trial platform for continuously testing multiple interventions. One lesson learned during the COVID-19 pandemic is that trial platforms can facilitate efficient execution of multicenter RCTs even in complex diseases during challenging conditions.¹⁷

In an aSAH trial platform, a master protocol would govern eligibility criteria, screening and randomization procedures, co-enrollment policies, choices of endpoints and definitions, blinding and endpoint ascertainment, and safety assessments and reporting. This would facilitate the study of multiple interventions in a perpetual manner, with treatments entering and leaving the platform based on pre-defined decision algorithms.¹⁸ The platform would allow for the possibility of multiple concurrent arms. Overall eligibility criteria would be broad, requiring only age ≥18 years and acute aSAH, and excluding only patients considered by the investigator to have a condition that precludes follow-up or safe participation or for whom written, informed consent cannot be obtained. Individual trial arms could have more restrictive eligibility criteria within this broad framework. The platform would be governed by one umbrella institutional review board protocol and clinical trial agreement, allowing individual arms to be efficiently added as amendments rather than stand-alone protocols and agreements. A standard set of case report forms based on NIH/NINDS common data elements for SAH with parsimonious adaptations for specific arms plus the general protocol standardization across trial arms would create synergies for data management and monitoring. Besides traditional endpoints such as the modified Rankin Scale score, a standardized system would be used to collect patient-reported outcomes in multiple domains. To address disparities and improve recruitment and retention, the platform would facilitate incorporation of screening and data collection modules into sites’ electronic medical record systems. A platform-wide Bayesian statistical analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility or lack of feasibility, common control arms and borrowing of information across arms whenever possible, and adaptive designs as appropriate. Such a design would still maintain rigor through randomization, blinding or blinded outcome assessment, an intent-to-treat population, a well-controlled false positive rate, and adjustments for treatment interactions and potential time trends. A protocol development committee would assist investigators and encourage pragmatic, open-label designs as much as possible given the numerous questions to be studied and the inherent difficulty of blinding for many of the proposed interventions; such designs would allow efficient and cost-effective trial execution and reduce study site burden. The protocol development committee would include patient and caregiver representatives, creating over time a community of previous trial participants who can provide peer-to-peer support for active trial participants.

Although not a systematic or exhaustive list, potential interventions and strategies that could be quickly and feasibly tested in an aSAH trial platform include:

1. Antiplatelet therapy or low-dose heparin to prevent microthrombosis.^19,20

2. Stellate ganglion block to prevent vasospasm.²¹

3. Lumbar drains to reduce hemorrhage volume and downstream effects such as vasospasm and delayed cerebral ischemia.¹¹

4. Intrathecal vasodilators to treat vasospasm.²²

5. Milrinone to augment cerebral blood flow in vasospasm.²³

6. Blood pressure augmentation targets in vasospasm.^24,25

7. Analgesic strategies for aSAH-related headache.²⁶

8. Beta-blockers to prevent neurocardiogenic injury.²⁷

9. PbtO₂ and microdialysis targets to maintain optimal brain perfusion.²⁸

10. Novel therapies to prevent early brain injury in aSAH.²⁹

11. Inhalational anesthetics as neuroprotective agents.³⁰

12. Hemoglobin targets for blood transfusion to optimize cerebral oxygen delivery.^31,32

13. Targeted temperature management to reduce secondary brain injury.³³

14. Choice of replacement fluid and mineralocorticoid supplementation for managing cerebral salt wasting and hypovolemia.^34,35

15. Combinations of therapies and bundles of care.

16. Nursing interventions.

An aSAH trial platform may be a means of better identifying effective new treatments for an important but relatively neglected type of stroke. By allowing efficient testing of numerous promising strategies, an aSAH trial platform is likely to result in effective new treatments that reduce the burden of long-term disability in the young and historically underrepresented population of patients with aSAH. In other cases, the results of trials in the platform would discourage the use of ineffective or harmful therapies which may otherwise be empirically adopted given the unmet needs and paucity of RCT data. Comparative effectiveness trials would lead to wider implementation of effective existing treatments and reduce practice variation. An aSAH trial platform is also likely to accelerate collaboration between government agencies, academia, and industry on promising early-stage neuroprotective agents and other therapeutics.

Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

Abbreviations

aSAH

Aneurysmal subarachnoid hemorrhage

COVID-19

Coronavirus disease 2019

NIH

National Institutes of Health

NINDS

National Institutes of Neurological Disorders and Stroke

PbtO₂

Partial brain tension of oxygen

RCT

Randomized clinical trial