In-silico trial of intracranial flow diverters replicates and expands insights from conventional clinical trials

Abstract Although the cost of clinical trials is ever-increasing, in-silico trials, which rely on virtual populations and interventions simulated using patient-specificc models, may offer a solution to contain these costs. However, in-silico trial endpoints need to be compared to those available from conventional clinical trials to ensure that the predictions of safety or effcacy from the in-silico approach are valid. Here, we present the flow diverter performance assessment (FDPASS) in-silico trial, which modelled the treatment of intracranial aneurysms in 82 virtual patients with a flow-diverting stent, using computational fluid dynamics (CFD) to quantify post-treatment flow reduction in the aneurysm sac. The predicted FD-PASS flow-diversion success rate replicated the values previously reported in three reference clinical trials. The in-silico approach allowed broader investigation of factors associated with insuficient flow reduction and increased stroke risk after flow diversion than would be feasible in a conventional trial. These ndings demonstrate for the rst time that in-silico trials of medical devices can (i) replicate ndings of conventional clinical trials and (ii) incorporate virtual experiments that are impossible in conventional trials.

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In-silico trial of intracranial flow diverters confirms and expands insights from conventional clinical trials

10.21203/rs.3.rs-147836/v1 ◽

2021 ◽

Author(s):

Ali Sarrami-Foroushani ◽

Toni Lassila ◽

Michael Macraild ◽

Joshua Asquith ◽

Kit C. B. Roes ◽

...

Keyword(s):

Clinical Trials ◽

In Silico ◽

Flow Diverter ◽

Flow Diversion ◽

Virtual Experiments ◽

Flow Reduction ◽

Trial Endpoints ◽

Computational Fluid Dynamics Cfd ◽

The Cost ◽

Flow Diverting Stent

Abstract Although the cost of clinical trials is ever-increasing, in-silico trials, which rely on virtual populations and interventions simulated using patient-specificc models, may offer a solution to contain these costs. However, in-silico trial endpoints need to be compared to those available from conventional clinical trials to ensure that the predictions of safety or effcacy from the in-silico approach are valid. Here, we present the flow diverter performance assessment (FDPASS) in-silico trial, which modelled the treatment of intracranial aneurysms in 82 virtual patients with a flow-diverting stent, using computational fluid dynamics (CFD) to quantify post-treatment flow reduction in the aneurysm sac. The predicted FD-PASS flow-diversion success rate replicated the values previously reported in three reference clinical trials. The in-silico approach allowed broader investigation of factors associated with insuficient flow reduction and increased stroke risk after flow diversion than would be feasible in a conventional trial. These ndings demonstrate for the rst time that in-silico trials of medical devices can (i) replicate ndings of conventional clinical trials and (ii) incorporate virtual experiments that are impossible in conventional trials.

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A Novel Flow Diverter for Direct Treatment of Cerebral Aneurysms

Volume 3: 16th International Conference on Advanced Vehicle Technologies; 11th International Conference on Design Education; 7th Frontiers in Biomedical Devices ◽

10.1115/detc2014-35699 ◽

2014 ◽

Author(s):

Jiayao Ma ◽

Thomas Peach ◽

Zhong You ◽

Rafik R. Rizkallah ◽

James Byrne

Keyword(s):

In Silico ◽

Cerebral Aneurysms ◽

Flow Diverter ◽

Flow Reduction ◽

Direct Treatment ◽

In Vivo Testing ◽

Biological Reaction ◽

Aneurysm Model ◽

Flow Diverting Stent

A summary of the manufacturing, in-silico and in-vivo testing of a laser cut cerebral flow-diverting stent (FDS) prototype is presented. The predicted flow-reduction achieved by both variants of the FDS design compares favorably with current commercially available designs. FDS design II is implanted into a swine aneurysm model to validate both the flow-diverting capability and a lack of adverse biological reaction.

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Increasing Flow Diversion for Cerebral Aneurysm Treatment Using a Single Flow Diverter

Neurosurgery ◽

10.1227/neu.0000000000000409 ◽

2014 ◽

Vol 75 (3) ◽

pp. 286-294 ◽

Cited By ~ 32

Author(s):

Jianping Xiang ◽

Ding Ma ◽

Kenneth V. Snyder ◽

Elad I. Levy ◽

Adnan H. Siddiqui ◽

...

Keyword(s):

Shear Stress ◽

Cerebral Aneurysms ◽

Flow Diverter ◽

Turnover Time ◽

Patient Specific ◽

Uniform Mesh ◽

Mesh Structure ◽

Flow Reduction ◽

Flow Stasis ◽

Single Flow

Abstract BACKGROUND: A neurovascular flow diverter (FD), aiming at inducing embolic occlusion of cerebral aneurysms through hemodynamic changes, can produce variable mesh densities owing to its flexible mesh structure. OBJECTIVE: To explore whether the hemodynamic outcome would differ by increasing FD local compaction across the aneurysm orifice. METHODS: We investigated deployment of a single FD using 2 clinical strategies: no compaction (the standard method) and maximum compaction across the aneurysm orifice (an emerging strategy). Using an advanced modeling technique, we simulated these strategies applied to a patient-specific wide-necked aneurysm model, resulting in a relatively uniform mesh with no compaction (C1) and maximum compaction (C2) at the aneurysm orifice. Pre- and posttreatment aneurysmal hemodynamics were analyzed using pulsatile computational fluid dynamics. Flow-stasis parameters and blood shear stress were calculated to assess the potential for aneurysm embolic occlusion. RESULTS: Flow streamlines, isovelocity, and wall shear stress distributions demonstrated enhanced aneurysmal flow reduction with C2. The average intra-aneurysmal flow velocity was 29% of pretreatment with C2 compared with 67% with C1. Aneurysmal flow turnover time was 237% and 134% of pretreatment for C2 and C1, respectively. Vortex core lines and oscillatory shear index distributions indicated that C2 decreased the aneurysmal flow complexity more than C1. Ultrahigh blood shear stress was observed near FD struts in inflow region for both C1 and C2. CONCLUSION: The emerging strategy of maximum FD compaction can double aneurysmal flow reduction, thereby accelerating aneurysm occlusion. Moreover, ultrahigh blood shear stress was observed through FD pores, which could potentially activate platelets as an additional aneurysmal thrombosis mechanism.

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In silico clinical trials: concepts and early adoptions

Briefings in Bioinformatics ◽

10.1093/bib/bby043 ◽

2018 ◽

Vol 20 (5) ◽

pp. 1699-1708 ◽

Cited By ~ 16

Author(s):

Francesco Pappalardo ◽

Giulia Russo ◽

Flora Musuamba Tshinanu ◽

Marco Viceconti

Keyword(s):

Clinical Trials ◽

In Silico ◽

Statistical Significance ◽

The United States ◽

Modelling And Simulation ◽

New Drugs ◽

Human Experimentation ◽

Partial Substitution ◽

Patient Specific ◽

Industrial Sectors

Abstract Innovations in information and communication technology infuse all branches of science, including life sciences. Nevertheless, healthcare is historically slow in adopting technological innovation, compared with other industrial sectors. In recent years, new approaches in modelling and simulation have started to provide important insights in biomedicine, opening the way for their potential use in the reduction, refinement and partial substitution of both animal and human experimentation. In light of this evidence, the European Parliament and the United States Congress made similar recommendations to their respective regulators to allow wider use of modelling and simulation within the regulatory process. In the context of in silico medicine, the term ‘in silico clinical trials’ refers to the development of patient-specific models to form virtual cohorts for testing the safety and/or efficacy of new drugs and of new medical devices. Moreover, it could be envisaged that a virtual set of patients could complement a clinical trial (reducing the number of enrolled patients and improving statistical significance), and/or advise clinical decisions. This article will review the current state of in silico clinical trials and outline directions for a full-scale adoption of patient-specific modelling and simulation in the regulatory evaluation of biomedical products. In particular, we will focus on the development of vaccine therapies, which represents, in our opinion, an ideal target for this innovative approach.

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A new imaging tool for realtime measurement of flow velocity in intracranial aneurysms

Clinics and Practice ◽

10.4081/cp.2017.975 ◽

2017 ◽

Vol 7 (3) ◽

Cited By ~ 1

Author(s):

Athanasios K. Petridis ◽

Marius Kaschner ◽

Jan F. Cornelius ◽

Marcel A. Kamp ◽

Angelo Tortora ◽

...

Keyword(s):

Real Time ◽

Fluid Velocity ◽

Flow Diverter ◽

Flow Dynamics ◽

Patient Specific ◽

Flow Profile ◽

Injection Speed ◽

Unruptured Aneurysms ◽

Flow Reduction ◽

Imaging Tool

With modern imaging modalities of the brain a significant number of unruptured aneurysms are detected. However, not every aneurysm is prone to rupture. Because treatment morbidity is about 10% it is crucial to identify unstable aneurysms for which treatment should be discussed. Recently, new imaging tools allow analysis of flow dynamics and wall stability have become available. It seems that they might provide additional data for better risk profiling. In this study we present a new imaging tool for analysis of flow dynamics, which calculates fluid velocity in an aneurysm (Phillips Electronics, N.V.). It may identify regions with high flow and calculate flow reduction after stenting of aneurysms. Contrast is injected with a stable injection speed of 2 mL/sec for 3 sec. Two clinical cases are illustrated. Velocity in aneurysms and areas of instability can be identified and calculated during angiography in real-time. After stenting and flow diverter deployment flow reduction in the internal carotid aneurysm was reduced by 60% and there was a reduction of about 65% in the posterior cerebral artery in the second case we are reporting. The dynamic flow software calculates the flow profile in the aneurysm immediately after contrast injection. It is a real-time, patient specific tool taking into account systole, diastole and flexibility of the vasculature. These factors are an improvement as compared to current models of computational flow dynamics. We think it is a highly efficient, user friendly tool. Further clinical studies are on their way.

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Artificial Intelligence Effecting a Paradigm Shift in Drug Development

SLAS TECHNOLOGY Translating Life Sciences Innovation ◽

10.1177/2472630320956931 ◽

2020 ◽

pp. 247263032095693

Author(s):

Masturah Bte Mohd Abdul Rashid

Keyword(s):

Artificial Intelligence ◽

Clinical Trials ◽

Drug Development ◽

Paradigm Shift ◽

Drug Repositioning ◽

Target Identification ◽

Success Rates ◽

Drug Target Identification ◽

The Cost ◽

Novel Drug

The inverse relationship between the cost of drug development and the successful integration of drugs into the market has resulted in the need for innovative solutions to overcome this burgeoning problem. This problem could be attributed to several factors, including the premature termination of clinical trials, regulatory factors, or decisions made in the earlier drug development processes. The introduction of artificial intelligence (AI) to accelerate and assist drug development has resulted in cheaper and more efficient processes, ultimately improving the success rates of clinical trials. This review aims to showcase and compare the different applications of AI technology that aid automation and improve success in drug development, particularly in novel drug target identification and design, drug repositioning, biomarker identification, and effective patient stratification, through exploration of different disease landscapes. In addition, it will also highlight how these technologies are translated into the clinic. This paradigm shift will lead to even greater advancements in the integration of AI in automating processes within drug development and discovery, enabling the probability and reality of attaining future precision and personalized medicine.

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Computational Hemodynamic Evaluation of Two Clinical Flow-Diverter Treatment Strategies: Overlapping Stents vs. Dense Compaction of a Single Stent

Volume 3: 16th International Conference on Advanced Vehicle Technologies; 11th International Conference on Design Education; 7th Frontiers in Biomedical Devices ◽

10.1115/detc2014-35716 ◽

2014 ◽

Author(s):

Robert Damiano ◽

Jianping Xiang ◽

Adnan Siddiqui ◽

Hui Meng

Keyword(s):

Treatment Strategies ◽

Flow Diverter ◽

Hemodynamic Effect ◽

Coverage Rate ◽

Patient Specific ◽

Test Cases ◽

Strongly Correlated ◽

Aneurysm Neck ◽

Computational Fluid Dynamics Cfd ◽

Flow Diverters

We employed computational fluid dynamics (CFD) and finite element method (FEM) to investigate the hemodynamic effect of two flow-diversion strategies of cerebral aneurysm treatment: overlapping stents and dense compaction of a single stent. Three representative patient-specific aneurysms were used as test cases, and flow diverters were virtually deployed into the models. Aneurysmal hemodynamic modification by flow diverters is strongly correlated with the metal coverage rate across the aneurysm neck, and not uniquely determined by FD deployment strategies. Fusiform aneurysms may be more favorable for achieving dense compaction for increased metal coverage rate than saccuclar aneurysms. To induce high flow reduction, the overlapping strategy may be more suitable for sidewall aneurysms, and the dense compaction strategy for fusiform aneurysms.

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Stroke Prevention in Non-Valvular Atrial Fibrillation

Hämostaseologie ◽

10.1055/s-0038-1659985 ◽

1997 ◽

Vol 17 (03) ◽

pp. 166-169

Author(s):

Judith O’Brien ◽

Wendy Klittich ◽

J. Jaime Caro

Keyword(s):

Atrial Fibrillation ◽

Clinical Trials ◽

Care Home ◽

Relevant Literature ◽

Clinical Trial Data ◽

Outcome Data ◽

Sensitivity Analyses ◽

Bleeding Events ◽

Discharge Data ◽

The Cost

SummaryDespite evidence from 6 major clinical trials that warfarin effectively prevents strokes in atrial fibrillation, clinicians and health care managers may remain reluctant to support anticoagulant prophylaxis because of its perceived costs. Yet, doing nothing also has a price. To assess this, we carried out a pharmacoe-conomic analysis of warfarin use in atrial fibrillation. The course of the disease, including the occurrence of cerebral and systemic emboli, intracranial and other major bleeding events, was modeled and a meta-analysis of the clinical trials and other relevant literature was carried out to estimate the required probabilities with and without warfarin use. The cost of managing each event, including acute and subsequent care, home care equipment and MD costs, was derived by estimating the cost per resource unit, the proportion consuming each resource and the volume of use. Unit costs and volumes of use were determined from established US government databases, all charges were adjusted using cost-to-charge ratios, and a 3% discount rate was applied to costs incurred beyond the first year. The proportions of patients consuming each resource were estimated by fitting a joint distribution to the clinical trial data, stroke outcome data from a recent Swedish study and aggregate ICD-9 specific, Massachusetts discharge data. If nothing is done, 3.2% more patients will suffer serious emboli annually and the expected annual cost of managing a patient will increase by DM 2,544 (1996 German Marks), from DM 4,366 to DM 6,910. Extensive multiway sensitivity analyses revealed that the higher price of doing nothing persists except for very extreme combinations of inputs unsupported by literature or clinical standards. The price of doing nothing is thus so high, both in health and economic terms, that cost-consciousness as well as clinical considerations mandate warfarin prophylaxis in atrial fibrillation.

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Exploring the Power and the Promise of In Silico Clinical Trials: Possible Applications in COVID-19 Pandemic

SSRN Electronic Journal ◽

10.2139/ssrn.3638283 ◽

2020 ◽

Author(s):

Abdelrahman H. Abdelmoneim ◽

Safinaz I. Khalil ◽

Hiba A. Osman ◽

Ayesan Rewane ◽

Sahar G. Elbage

Keyword(s):

Clinical Trials ◽

In Silico

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