Study design of Real World Evidence for Treatment of Hyperkalemia in the Emergency Department (REVEAL-ED): a multicenter, prospective, observational study on behalf of the REVEAL-ED study investigators
October 15-19, 2016

Zubaid Rafique email@example.com
Mikhail Kosiborod
Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City
Kansas CityMOUSA

Carol L Clark
Beaumont Hospital-Royal Oak, Royal Oak
MIUSA

Adam J Singer
Stony Brook School of Medicine
Stony BrookNYUSA

Stewart Turner
ZS Pharma, Inc
San MateoCAUSA

Joseph Miller
Henry Ford Hospital
DetroitMIUSA

Douglas Char
College of Medicine
Washington University
1504, 77030Saint Louis, Ben Taub Loop, HoustonMO, TXUSA, USA

W Frank Peacock
Ben
General Hospital, BaylorBen Taub

Taub General Hospital
Baylor College of Medicine
HoustonTXUSA

Study design of Real World Evidence for Treatment of Hyperkalemia in the Emergency Department (REVEAL-ED): a multicenter, prospective, observational study on behalf of the REVEAL-ED study investigators
October 15-19, 201610.15441/ceem.17.207Received: 1 February 2017 Revised: 26 March 2017 Accepted: 28 March 2017 Correspondence to: Zubaid Rafique154 Original Article This study was presented at Society for Academic Emergency Medicine 2016 meeting, May 10-13, 2016 in New Orleans, LA; American College of Emergency Physicians 2016 meeting,HyperkalemiaPotassiumElectrolyte disturbance
Objective Hyperkalemia affects up to 10% of hospitalized patients and, if left untreated, can lead to serious cardiac arrhythmias or death. Although hyperkalemia is frequently encountered in the emergency department (ED), and is potentially life-threatening, standard of care for the treatment is poorly defined, with little supporting evidence. The main objectives of this observational study are to define the overall burden of hyperkalemia in the ED setting, describe its causes, the variability in treatment patterns and characterize the effectiveness and safety of ED standard of care therapies used in the United States.Methods This is an observational study evaluating the management of hyperkalemia in the ED. Two hundred and three patients who presented to the ED with a potassium value ≥5.5 mmol/L were enrolled in the study at 14 sites across the United States. Patients were treated per standard of care practices at the discretion of the patient's physician. In patients who received a treatment for hyperkalemia, blood samples were drawn at pre-specified time points and serum potassium values were recorded. The change in potassium over 4 hours and the adverse events after standard of care treatment were analyzed.Results and ConclusionThis article describes the background, rationale, study design, and methodology of the REVEAL-ED (Real World Evidence for Treatment of Hyperkalemia in the Emergency Department) trial, a multicenter, prospective, observational study evaluating contemporary management of patients admitted to the ED with hyperkalemia.

INTRODUCTION

Hyperkalemia occurs in up to 10% of hospitalized patients. [1][2][3][4] Patients with chronic kidney disease and cardiovascular disease, as well as those who are treated with renin-angiotensin-aldosterone system inhibitors, are at greater risk of hyperkalemia. 5,6 The prevalence of hyperkalemia and related hospitalizations are on the rise in parallel with increased use of renin-angiotensin-aldosterone system inhibitors and an aging hospitalized patient population. 7 Patients are often sent to the emergency department (ED) due to high potassium levels, and over 800,000 hyperkalemia-related ED visits are estimated to occur annually in the US. 8 If left untreated, hyperkalemia can lead to life-threatening cardiac arrhythmias, [9][10][11] and is associated with substantially increased risk of death. [12][13][14] One study reported in-hospital mortality of patients with hyperkalemia to be as high as 18.1%, while those with normal potassium to be 3.9%. 13 Several other studies have also shown an increase in the risk of death for serum potassium levels above 5 mmol/L and a rapid increase in the risk of death as serum potassium levels exceed 5.5 mmol/L. 6,14,15 In particular, a study by Grodzinsky el al. 15 reported that in-hospital mortality was greater than 15% once the maximum potassium level was above 5.5 mmol/L, and another study by Einhorn et al. 6 reported a 1-day mortality rate up to 17 times higher for hospitalized patients with potassium levels > 6.0, as compared to < 5.5 mmol/L.

Although no randomized trials on hyperkalemia treatments and their impact on in-hospital mortality have been conducted, available observational data suggest that reducing potassium levels in patients with hyperkalemia may lower mortality risk. For example, an observational cohort study at two medical centers in Korea found that treatment of patients with hyperkalemia with common therapies excluding dialysis, improved serum potassium levels and had a positive association with better survival. 16 A separate observational study of hospitalized patients who received critical care at two tertiary care hospitals in Boston, MA, showed that a reduction of 1 mmol/L or greater in serum potassium with-in 48 hours after hospitalization was associated with decreased mortality risk. 17 In addition, a retrospective study of 38,689 consecutive patients with acute myocardial infarction found that inhospital mortality was twice as high among hyperkalemic patients whose potassium levels remained high compared to patients whose potassium levels returned to a normal range. 15 Although hyperkalemia is frequently encountered in the ED, and is potentially life-threatening, a standard of care (SOC) for hyperkalemia treatment is poorly defined. Acute pharmacologic treatment options for hyperkalemia are limited and their use is complicated by suboptimal tolerability and safety and uncertain efficacy. Hemodialysis is effective for the treatment of hyperkalemia, but is invasive and costly, and significant logistical issues must be overcome in order to initiate this in the ED. In addition, the emergency management of hyperkalemia is not consistent across clinicians and institutions in the US. 18 A Cochrane review of emergency management of hyperkalemia suggested that sufficient randomized, controlled trials supporting the use of commonly prescribed therapies are lacking and many of the trials are methodologically flawed. 18 Accordingly, we conducted a multicenter, prospective, observational study to define the overall burden of hyperkalemia in the ED setting, describe its causes, and variability in treatment patterns and characterize the effectiveness and safety of ED SOC therapies used in the US. We hypothesized that SOC treatment of hyperkalemia is variable and multiple medications are used in the acute setting. We further hypothesized that all SOC medications are effective in the first four hours of treatment. To our knowledge, this is the first prospective, rigorously designed observational study directly addressing gaps in knowledge in the US.

METHODS

Study design

The Real World Evidence for Treatment of Hyperkalemia in the Emergency Department (REVEAL-ED) is a multicenter, prospec-

What is already known

Hyperkalemia is frequently encountered in the emergency department and is potentially life threatening. Standard-ofcare treatment for hyperkalemia is limited and poorly defined.

What is new in the current study

This is the first prospective, observational study addressing gaps in knowledge in hyperkalemia treatment. This article describes the background, rational and methodology of the REVEAL-ED (Real World Evidence for Treatment of Hyperkalemia in the Emergency Department) trial.

REVEAL-ED study methods

tive, observational study evaluating the management of patients admitted to the ED with hyperkalemia. The study was approved by the institutional review board or local ethics committee for each site and registered at ClinicalTrials.gov (NCT02607085). Each patient, legally authorized guardian, or a person with legal responsibility for the patient's health care decisions provided written informed consent prior to participation in any study activities.

Study setting and population

From October 25, 2015 to March 30, 2016, a total of 203 patients who presented to the ED with a potassium value ≥ 5.5 mmol/L were enrolled in the study at 14 sites across the US (Fig. 1). Eligible patients were ≥ 18 years of age, provided written informed consent, and had hyperkalemia confirmed in the ED with a documented potassium ≥ 5.5 mmol/L. Enrollment of patients with a baseline potassium < 6.0 mmol/L was limited to 50 patients, after which the entry criteria required a baseline potassium ≥ 6.0 mmol/L. A point-of-care analyzer was allowed to determine the baseline potassium level if this was the standard practice at that site. Patients were excluded from the study if, in the opinion of the treating physician, they were unable to perform the tasks associated with the protocol, they were participating in another clinical study which could impact the REVEAL-ED study or they had been previously enrolled in this study.

Study protocol

After patients provided written informed consent, their demographics and medical history data, including previous ED visits and hospital admissions for hyperkalemia, were recorded. Patients with a prior history of heart failure were classified according to the New York Heart Association functional classification system.

The baseline study-related whole blood potassium was deter- mined using a point-of-care device (i-STAT; Abbott Point of Care, Princeton, NJ, USA), provided by the sponsor, prior to the first intervention for hyperkalemia. If no baseline study-related potassium value was obtained, then the potassium value qualifying the patient for study entry was considered as the patient's baseline. If the SOC potassium value qualifying the patient for the study was ≥ 5.5 mmol/L, but the baseline i-STAT value was < 5.5 mmol/L then the SOC value was recorded and the patient was allowed to remain in the study.

In patients who received a treatment for hyperkalemia, studyrelated potassium samples were drawn and analyzed by i-STAT at 0.5, 1, 2, 4, 8, 12, and 24 hours after intervention initiation (Fig.  2). If a patient was transferred from the ED to another hospital location, then research staff continued to collect study-related i-STAT samples to the extent feasible. If a patient received more than one intervention for hyperkalemia, then the post-treatment potassium measurement schedule started from the initiation of the first intervention, except if a patient received sodium polystyrene sulfonate, then additional study-related potassium samples were drawn at 1, 2, and 4 hours following initial sodium polystyrene sulfonate administration.

In patients who received no intervention during the initial 4-hour period, study-related potassium samples were drawn and analyzed by i-STAT at 4, 8, 12, and 24 hours after the SOC potassium measurement qualifying the patient for study entry. If a patient was transferred from the ED to another hospital location, then the site continued to collect study-related i-STAT samples to the extent feasible.

Patients were treated per SOC practices at the discretion of the patient's physician. Any medication administered as part of SOC practice was provided according to the drug dispensing policy at each investigational site. No specific treatment algorithms were prescribed by the study protocol, and no medications were supplied by the sponsor during the study. Available data obtained as part of ED SOC management were recorded upon ED admission and up to 24 hours after the initial intervention, or through 24 hours after the potassium measurement that qualified the patient for entry into the study if no intervention was performed. Available SOC management data that was recorded included physical examinations, vital signs, fluid intake and urine output, electrocardiograms, clinical laboratory data, and results of chest X-rays. Data regarding the patient's chief complaint upon ED admission, possible cause of the patient's hyperkalemia, as well as admitting and discharge diagnoses were recorded. The patient's overall discharge summary and hospital discharge time were also collected when possible.

The timing of each hyperkalemia intervention following ED admission as well as the dose and route of administration were recorded. Concomitant medications were collected for the 14 days before ED admission through ED discharge. If a patient was admitted to another hospital location (i.e., to an in-patient bed), medications administered after ED evaluation was collected for up to seven days or until discharge from the hospital, whichever came first.

Dates and times were recorded for the following (if applicable): ED admission, hospital admission, intensive care unit admission, observation unit admission, step down unit admission, regular floor admission, discharge (from all admissions), dialysis, do not resuscitate order entry, death, and any other recordable outcome deemed significant by the investigator.

Recordable outcomes were limited to pulmonary edema, ventricular tachycardia/fibrillation, pulseless electrical activity arrest, new clinically significant electrocardiogram changes (specifically including but not limited to severe bradycardia, advanced heart block, bundle branch block, tachycardia [> 100 bpm]), palpitations, hypoglycemia, and gastrointestinal-related events (e.g., nausea, vomiting, diarrhea) and any other event deemed significant by the investigator. Recordable outcomes requiring positive-pressure ventilation, central venous access, intubation, chest compressions, intravenous (IV) vasopressors, IV vasodilators, IV anti-arrhythmics, and/or emergency dialysis or resulting in death were also collected. These outcomes were recorded from the time of ED admission through ED discharge. If a patient was admitted to another hospital location, post-ED recordable outcomes were collected for up to 7 days following admission to that unit or until hospital discharge, if earlier. Recordable outcomes resulting in death while the patient remained in the hospital were collected for up to 30 days after ED admission.

Outcome measures

The primary endpoint of the study was the absolute change in potassium over 4 hours following the initial intervention for hyperkalemia. If a patient did not receive an intervention for hyperkalemia during the ED admission, then the change over 4 hours following the baseline potassium measurement was used.

Secondary endpoints included the rate of change in potassium over 4 hours following the initial intervention for hyperkalemia, change in potassium at other time points (rate, percent and absolute), choice of intervention, timing and details of procedures relative to ED admission, other outcome events (e.g., hospital and intensive care unit admissions, cardiac arrhythmias and conduction abnormalities, hemodynamic instability/cardiac arrest, inhospital deaths), as well as safety and tolerability of SOC interventions were also evaluated.

Data analysis

No formal sample size calculation was performed for this study. A sample size of 200 patients was selected based on clinical judgement and was considered sufficient to adequately characterize the different interventions in this population. The study populations for analysis include the intent-to-treat and safety populations. The intent-to-treat population included all patients enrolled in the study with any post-baseline study-related potassium values. The safety population included all patients enrolled in the study who had any post-baseline follow-up for safety.

Changes in study-related potassium values following an intervention were used to assess efficacy. All analyses were based on the study-related potassium results obtained using i-STAT. Safety was evaluated using recordable outcomes, clinical laboratory parameters, vital signs, fluid intake and urine output, physical examination, electrocardiograms, and chest X-rays. The principle of treatment emergence was employed for the analysis of recordable outcome data. Treatment emergence was defined to be any event that occurred during the observation period of the study and was not present at baseline, or one that represents an exacerbation of a condition present at baseline.

Recordable outcomes were classified by the medical dictionary for regulatory activities (MedDRA). The type, incidence, timing (onset and duration), relationship to hyperkalemia and to intervention for hyperkalemia, and severity of recordable outcome was reported for treatment-emergent outcomes. Reasons for withdrawal due to recordable outcomes were also reported. The incidence of clinically significant cardiac events (e.g., cardiac arrhythmia, cardiac arrest, cardiovascular and all-cause death) was calculated. All cardiac events were adjudicated by an independent review committee prior to database lock using available SOC data for each case. Descriptive statistics will be presented overall for the study population, as well as stratified by potassium levels at baseline, and by treatment group. When appropriate, hierarchical multivariable analyses will be performed adjusting for differences in patient characteristics and hospital site.

Role of the sponsor

The study sponsor participated in developing the study design, conducted data collection, and will participate in data analyses. The study investigators and all authors provided critical input for the study design and methodology, will have free access to the study data, will lead the analysis and interpretation of the data, and have sole discretion in the writing of the report and the decision to submit the manuscript for publication.

DISCUSSION

Hyperkalemia is frequently encountered in the ED and can lead to cardiac arrhythmias or death. Emergency management of hyperkalemia and close monitoring in the hospital setting is often necessary, but SOC for hyperkalemia has not been well characterized. To our knowledge, this is the first prospective, rigorously designed observational study directly addressing the gaps in knowledge of hyperkalemia management in the United States.

A few noteworthy points about our methodology are as follows: First, our primary end point is to measure the effect of an emergent intervention in the first 4 hours. This time-line was chosen to evaluate how quickly the SOC intervention is effective, as severe hyperkalemia can be lethal and quick interventions are needed in the emergency setting. Moreover, this time frame made the study feasible to conduct in the ED setting. Second, we enrolled only fifty patients with a potassium range ≥ 5.5 mmol/L and < 6.0 mmol/L because we wanted to see the effectiveness of the interventions at higher potassium levels. Lastly, even though this was an ED based study and we were interested in the effectiveness of interventions in the first 4 hours, we collected data up to 7 days after admission, when applicable, so we could evaluate some of the lasting side effects of the SOC interventions.

This study has several limitations inherent to the nature of an observational study design. For instance, patients were not randomized to the different interventions since they were treated per SOC practices at the discretion of the patient's physician. Also, the medications administered as part of SOC practice were not standardized across investigational sites as medications were provided according to the hospital standards at each investigational site. Hence, we expect to find different dosages of the same medication being used at different sites. The observational design of the study allows for an accurate description of the current SOC therapies used to treat hyperkalemia in the US, but the study is not designed to directly compare the efficacy of these interventions.

In summary, the REVEAL-ED study seeks to define the overall burden of hyperkalemia in the ED setting and will describe the variability in treatment patterns as well as characterize the effectiveness and safety of ED SOC therapies used to treat hyperkalemia in the US.

Fig. 1 .
1REVEAL-ED (Real World Evidence for Treatment of Hyperkalemia in the Emergency Department) study sites. Marked areas on the map represent study sites in the US.

Fig. 2 .
2Study design.Screening: (1) Standard of care potassium, (2) subject's chief complaints upon arrival at emergency department, (3) assess possible cause of hyperkalemia, and (4) New York Heart Association assessment if history of heart failure. Initial intervention/treatment Blood draws to measure potassium levels Concomitant medications assessment Zubaid Rafique, et al.
Clin Exp Emerg Med 2017;4(3):154-159
ACKNOWLEDGMENTSThis study was sponsored and funded by ZS Pharma, Jessica Mendoza, PhD, an employee of ZS Pharma provided editorial assistance for the preparation of this manuscript. David Morris of Webb Writes provided statistical support for this study and received consulting fees from ZS Pharma for this work.CONFLICT OF INTERESTNo potential conflict of interest relevant to this article was reported.
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Serum potassium levels as an outcome determinant in acute medical admissions. R Conway, D Creagh, D G Byrne, D O'riordan, B Silke, Clin Med. 15Conway R, Creagh D, Byrne DG, O'Riordan D, Silke B. Serum potassium levels as an outcome determinant in acute medical admissions. Clin Med 2015;15:239-43.

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He holds a PhD in Solid Mechanics (1996) and a BEng in applied mechanics
1992

Alessandro Schiavone
Tian-Yang Qiu
Li-Guo Zhao firstname.lastname@example.com

Electrical and Manufacturing Engineering
Wolfson School of Mechanical, Electrical and Manufacturing Engineering
Wolfson School of Mechanical
Loughborough University
LE11 3TULoughboroughUK

Loughborough University
LE11 3TULoughboroughUK

He holds a PhD in Solid Mechanics (1996) and a BEng in applied mechanics
19921 Correspondence to: Prof. Li-Guo Zhao, Vessel Plus 2017 Jan 19. [Online First] Quick Response Code: Original Article Open Access Schiavone et al. Vessel Plus 2017 Jan 19. [Online First] www.vpjournal.net This is an open access article licensed under the terms of Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original author is credited and the new creations are licensed under the identical terms. For reprints contact: Prof. Li-Guo Zhao is a ProfessorPolymeric stentsmetallic stentsfinite elementcrimpingdeployment
How to cite this article: Schiavone A, Qiu TY, Zhao LG. Crimping and deployment of metallic and polymeric stents --finite element modelling.Aim: This paper aims to compare the mechanical performance of metallic (Xience) and bioresorbable polymeric (Elixir) stents during the process of crimping and deployment. Methods: Finite element software ABAQUS was used to create the geometrical models and meshes for the balloon, stent and diseased artery. To simulate the crimping of stents, 12 rigid plates were generated around the stent and subjected to radially enforced displacement. The deployment of both stents was simulated by applying internal pressure to the balloon, where hard contacts were defined between balloon, stent and diseased artery. Results: Elixir stent exhibited a lower expansion rate than Xience stent during deployment. The stent diameter achieved after balloon deflation was found smaller for Elixir stent due to higher recoiling. Lower level of stresses was found in the plaque and artery when expanded by Elixir stent. Reduced expansion, increased dogboning and decreased vessel stresses were obtained when considering the crimping-generated residual stresses in the simulations. Conclusion: There is a challenge for polymeric stents to match the mechanical performance of metallic stents. However, polymeric stents impose lower stresses to the artery system due to less property mismatch between polymers and arterial tissues, which could be clinically beneficial.ABSTRACTArticle history:

INTRODUCTION

Over the past three decades, significant improvements have been made in stent designs and materials, especially the development of drug-eluting stents (DESs, approved by Food and Drug Administration (FDA) of USA in 2002). The vast majority of DESs used so far have non-degradable polymer coatings, incorporated with anti-proliferative drugs, to overcome the notorious in-stent restenosis (ISR) that represented an undesired drawback of bare metal stents. [1] Although ISR rates can be substantially reduced by DESs (lowered by 74% in high-risk patients), the lifelong presence of metallic alloy stents, under loads and corrosive conditions, could increase the risk of strut fracture and failure with time. This may lead to possible complications such as delayed healing, lethal migration and unstable angina. [2,3] Bioresorbable stents provide the advance of overcoming these possible longterm complications of metallic stents. Biodegradable polymers are the most promising materials investigated to date. [4][5][6] Fully expandable polymeric biodegradable stents initially support the vessel wall as scaffolds with sufficient radial strength to prevent mechanic recoil after implantation. In about 6 months, arterial remodelling enters a stable phase, and no substantial scaffolding is required. Consequently, it is desirable for stents to dissolve after 6 months in the body, leaving behind an intact vessel with no pro-inflammatory substances or obstacles for future treatments. [7] During the process, the polymers gradually soften, which allows for a smooth disappearance of high stresses, imposed by the permanent stents, in the recovering artery. It should be noted that recent reports have suggested an independent relationship between bioresorbable stents and stent thrombosis. [8] Instead, the higher incidence rates of stent thrombosis were associated with the 2.5 mm platforms. [9] One of the major concerns for polymeric BRSs is their mechanical performance, especially their interaction with blood vessels during and after deployment. Agrawal et al. [10] carried out the earliest work in assessing the in vitro performance of the Duke biodegradable stents made of Poly-L lactide (PLLA) fibres. Results showed that a successful biodegradable stent could be achieved by carefully balancing the mechanical properties of PLLA fibres and geometrical design of stents. Nuutinen et al. [11] conducted in vitro tests of a woven fibre polymeric braided stent subjected to radial compression. The performance of such stents was not as good as metal ones, and the collapse pressure was found lower, even for thicker PLLA fibres. Bünger et al. [12] compared the in vivo performance of stents made of biodegradable PLLA and stainless steel, by monitoring the stents after the implantation in carotid arteries of living pigs. Both stents achieved initial technical success. However, PLLA was reported to be significantly softer than metallic alloys, which affected the radial stiffness of the implanted stents and needed to be further investigated. Over the last two decades, great effort has been made for the development of bioresorbable stents, and there have been many devices available in preclinical and clinical evaluations. Elixir DESolve (Elixir Medical Corporation, USA) stent, made of PLLA, is one of the major biodegradable stents currently available on the market. The polymer stents showed sufficient radial strength within 6 months of implantation, with the occurrence of bioresorption between one and two years. [13] Finite element (FE) analyses have been largely used in modelling of stent expansion and deformation during the deployment process. [14][15][16] However, majority FE analyses were performed on metallic stents. For example, Imani et al. [17] modelled the effects of design on vessel wall stresses for Palmaz-Schatz, Xience V and NIR stents. The comparative study confirmed that Palmaz-Schatz stent generated 15.6% and 7.6% higher stresses in the arterial wall than Xience V stent and NIR stent, respectively. The results suggested a direct correlation between vessel wall stresses and in-stent restenosis rate, as Palmaz-Schatz stent gave the highest restenosis rate in clinical trials. Recent FE simulations on metallic stents by Schiavone et al. [18] also confirmed that stent design is a major factor that controls the expansion of the device and also the stresses generated in the artery. In addition, shape optimization of metallic stents, in terms of improved fatigue resistance and radial flexibility, can also be achieved by FE modelling. [19] On the contrary, there is very limited work dedicated to modelling the deformation of bioresorbable polymer stents, particularly during the process of deployment in diseased arteries.

In this paper, FE modelling was carried out to simulate the deployment of Elixir polymer stent in a diseased artery, with head-to-head comparison against Xience metallic stent. Particularly, the simulations considered the crimping step, which is necessary to fix the asproduced stent to the catheter. The mechanical performance of the two stents has been compared directly, in terms of radial expansion and stresses in the stent-vessel system. In addition, results were also compared with those obtained without considering the residual stresses generated from the crimping process.

METHODS

Models for stents, balloon and artery

Geometries for Xience and Elixir stents were built using the NX design software. Both stents were created in expanded shape, with a diameter of 3 mm and a length of 10 mm. The geometries of both stents were based on dimensions found in open resource. The strut thickness is 80 µm and 150 µm for Xience stent and Elixir stent, respectively. The FE mesh contains eight-node incompatible brick elements, with full integration (C3D8I). The incompatible mode is chosen for the purpose of modelling large bending deformation during stent crimping and subsequent expansion. There are 4-layer elements through the width and the thickness of all struts. The geometrical designs and FE meshes for both stents are given in Figure 1.

The balloon used to inflate the stents had a tri-folded geometry which was produced using the NX software. The diameter of the fully folded part is 1.25 mm and the total length of the balloon is 14 mm. To create the pattern, the tri-folded cross section was sketched first, and subsequently extruded for a length of 12 mm. Towards the ends, the balloon smoothly transits into a circle, 0.75 mm in diameter, over a length of 1 mm. This was done by using the sweeping tools in NX. The balloon was totally constrained at both ends as they are fixed to a catheter. The diameter of the expanded balloon was set to be 3 mm, matching the targeted stent or vessel diameter after deployment. Four-node shell elements, with reduced integration (S4R), were adopted to mesh the tri-folded balloon.

The diseased artery has a total length of 40 mm and a lumen diameter of 3 mm for the heathy part. The middle portion of the artery is covered by 10 mm plaque. The stenosis, defined as the ratio of plaque thickness to healthy lumen radius, was chosen to be 50%. The artery comprises three individual tissue layers, and the wall thickness is 0.27 mm, 0.35 mm and 0.38 mm for the intima, media and adventitia layers, respectively. Eight-node brick elements with reduced integration (C3D8R) were used to mesh the artery and the plaque. Four layers of elements were assigned through the wall of each tissue layer and eight layers of elements were assigned through the plaque thickness.

Geometry and mesh of the balloon-artery assembly are shown in Figure 2. Mesh-sensitivity studies confirmed the convergence of numerical results, with regards to stent expansion, stent recoiling and stresses in the stent-artery system, for the mesh adopted in this work.

Material model

Both stents were modelled as elastic-plastic, with nonlinear strain hardening [ Figure 3]. The tensile stressstrain curves for Co-Cr L605 and PLLA were taken from literature. [20,21] It can be noted that PLLA is much weaker than Co-Cr L605. Table 1 gives the essential properties for both materials as obtained from the tensile curves. Strain hardening was realised in ABAQUS by stating the yield stress as a function of the plastic strain, as also obtained from the tensile curves. The plaque was assumed to be hypocellular, and its behaviour was described by the Ogden hyperelastic model. The hyperelastic model parameters were provided in Zahedmanesh and Lally. [22] The tri-folded balloon was treated as a linear elastic material. The material density, Young's modulus and Poisson's ratio were taken as 1.1 × 10 6 kg/mm 3 , 900 MPa and 0.3, respectively. [23] It is well recognised that the arterial layers possess distinct anisotropic behaviour as they are reinforced by two families of collagen fibres. Here, the established Holzapfel-Gasser-Ogden (HGO) anisotropic hyperelastic model [24] was employed to describe the anisotropic behaviour of individual coronary arterial layer. In this model, the hyperelastic strain energy potential W is given by: [24]
W = C 10 (I 1 -3) + (k 1 /2k 2 )[exp(k 2 <E f > 2 ) -1] + (1/D)[(J 2 -1)/2 -lnJ] E f = k(I 1 -3) + (1 -3k)(I 4 -1)
where C 10 , D, k 1 , k 2 and k are model parameters, I 1 and J are the first and third stretch invariants, and I 4 is the invariant of Cauchy-Green deformation tensor. The Macauley bracket is indicated by the operator <>, whilst γ represents the angle between the mean directions of the two families of fibres whose deformation is defined by E f . The model parameters [ Table 2] were calibrated against the experimental data. [25] Both longitudinal and circumferential stress-stretch responses, computed by using the HGO model, agreed with the experimental data very well [25] for all three vessel layers [ Figure 4].

The HGO model used in this work is for incompressible hyperelastic materials. To consider compressible deformation, the HGO-C model was suggested, with the anisotropic part expressed by isochoric invariants  (insensitive to volumetric deformation). However, Nolan et al. [26] found that the HGO-C model was unable to simulate compressible anisotropic behavior correctly, because it used isochoric anisotropic invariants which is insensitive to volumetric deformation. Consequently, they formulated a modified anisotropic (MA) model by using the full anisotropic invariants which accounted for a volumetric anisotropic contribution. The MA model correctly predicted the material's anisotropic response to hydrostatic tensile loading, pure shear and uniaxial deformations. They also found the HGO-C model significantly underpredicted arterial compliance, which might affect the simulation results of stent deployment in diseased arteries. To fully clarify this effect, a considerable amount of new work is required, especially the efforts required for coding a user-defined material subroutine for the MA model (interface with the FE package Abaqus). This is beyond the scope of this paper, and will be investigated in our future studies.

Nevertheless, the HGO model used in this work was calibrated properly against the longitudinal and circumferential tensile data of arteries. [25] It was proved to be a reliable anisotropic formulation for modeling deformation of the arterial layers with collagen fibre reinforcement.

Crimping simulation

To model stent crimping, twelve rigid plates were generated around the stent as shown in Figure 5. The rigid plates were modelled as shell surfaces. Uniform radial displacement, linearly increasing to 1 mm within a step time of 0.1 s, was applied to the plates to enforce the crimping of stent. Spring back of the stent after crimping, due to the recovery of elastic deformation, resulted in a final stent diameter of 1.5 mm, which is able to fit in the diseased vessel.

Abaqus explicit was adopted for crimping simulations (0.1 s step time). No constraint was applied to the stent. Hard contact was assigned between the outer surface of the stent and the rigid plates. The friction coefficient was assumed to be 0.8. Following crimping, an additional step was used to simulate the spring back of the stent within 0.1 s. In this step, the contacts between the rigid plates and the stent were deleted, allowing for the stent to recover the elastic deformation freely.

Expansion simulation

The expansion procedure was simulated using two steps, namely inflation and deflation. During the inflation step (0.1 s), a pressure linearly increasing to 1.2 MPa was applied inside the balloon. While in the deflation step (0.1 s), the balloon pressure was brought linearly down to zero. All analyses were carried out by considering the residual stresses generated from crimping. Again, simulations were performed using the explicit solver in Abaqus. Change of stent outer diameter was tracked for the middle ring and the two end rings of both stents. The data outputs were used to quantify stent expansion as well as the recoiling and dogboning effects. [27]

RESULTS

Stent crimping

During crimping, both stents underwent severe bending deformation, as illustrated in Figure 6 for Elixir stent. The two stents were squashed to a diameter of only 1.25 mm at the fully crimped state. After crimping, stresses were highly localised at the U-bend regions for both devices. The von Mises stress in the Xience and the Elixir stents had a maximum magnitude of 750 MPa [ Figure 7A right] and 96 MPa [ Figure 7A left], respectively. After spring back, the maximum von  [20,21] Mises stress in the Xience and Elixir stents relaxed to 706 MPa and 50 MPa, respectively [ Figure 7B]. These are also the residual stresses generated in the stent after crimping. And the diameter of both stents settled at about 1.5 mm.

Stent expansion

Pressure-diameter plots in Figure 8 showed that Elixir stent experienced a lower rate of expansion than Xience stent. Both stents developed a saturation state in expansion with the increasing pressure, but Elixir stent reached the saturation earlier. At the maximum pressure, the stent outer diameter was computed as 2.66 mm and 2.61 mm for the Xience and Elixir stents, respectively. The recoiling effect was 11% for the Xience stent [ Figure 8B], which is significantly lower than that for the Elixir stent (20%; Figure 8B). Consequently, a larger final diameter was achieved for the Xience stent (2.40 mm) when compared to the Elixir stent (2.10 mm only). Consistently, the Xience stent also showed considerably less dogboning effect (24%) than the Elixir stent (45%).

High levels of stresses were developed in both stents following their deployment in the artery [ Figure 9]. Similar to the crimping process, the maximum von Mises stresses were found in the U-bend districts, with a value of 935 MPa for the Xience and 95 MPa for the Elixir stent. In the artery, the peak stresses were generally found on the plaque, especially towards the ends of the stenosis. This was caused by the dogboning effect of the implanted stent. There is a direct connection between stress concentration and localized rupture for plaque as evidenced in numerous studies. [28,29] In our case, plaque rupture is likely to happen towards the ends of plaque region, a condition that can lead to heart attack (coronary artery) or stroke (carotid artery). In addition, there could be  The maximum principal stress on the plaque had a peak value of 1.43 MPa and 0.54 MPa for the Xience and Elixir stents, respectively [ Figure 10]. The considerably lower stress level for Elixir stent is consistent with the reduced property mismatch between the polymer and the artery as well as less arterial expansion achieved by the polymer stent. It should be noted that stress triaxiality was not explored for the stents and diseased artery. Stress triaxiality is defined as the ratio of hydrostatic stress to the equivalent (or von Mises) stress, and it is a key parameter used in ductile fracture analysis. In this study, we mainly focus on the stress state of stent-artery system during crimping and expansion, instead of fracture or failure. Consequently, stress triaxiality is not presented. But we aim to look into this in future studies when considering the failure and fracture of stent, plaque and arteries in the simulations.

Effect of residual stresses caused by crimping

As shown in Figure 7, crimping introduced severe residual stresses into the stent, which can affect the subsequent expansion of the device. To understand such effect, simulations of stent deployment were also carried out for both stents without including the residual stresses generated from crimping.  For Elixir stent, it is confirmed that crimping-caused residual stresses do affect stent expansion [ Figure 11]. When stent expansion was simulated without considering residual stress, the stent expanded faster and reached saturation earlier, as shown by the solid blue line in Figure 11A. Overall, residual stresses tend to compromise stent expansion both at peak pressure and after balloon deflation. At peak pressure, stent outer diameter was found to be 2.61 mm and 2.75 mm for simulations with and without considering residual stresses, respectively, and settled as 2.10 mm and 2.19 mm, respectively, after balloon deflation.

Although the recoiling had similar magnitude for both cases (~20%; with and without residual stresses), less dogboning was found when residual stresses were excluded in simulations (i.e. 41%; versus 45% for simulations with residual stresses). As shown in Figure 12, residual stresses did not affect the pattern of stress distribution in the stent and artery. On the stent, stresses are still highly localised at the U-bend regions, regardless of the residual stress state. Also, the maximum stress on the stent changed only by ~0.4% (95.69 to 95.32 MPa) when residual stresses were considered in the simulations. In the artery [ Figure 12B], stresses were again concentrated towards the ends of the plaque as a result of stent dogboning effect. The peak value of the maximum principal stress changed by ~15% (0.64 to 0.54 MPa) when the residual stresses were included.

For Xience stent, residual stresses affected the early stage of expansion of the stent as shown in Figure 13. The achieved final diameter (~2.40 mm) and the recoiling effect (~11%) were similar for the two cases (with and without residual stresses). Dogboning increased when residual stresses were excluded, with a value of 36% (compared to 24% for the case considering residual stresses). As shown in Figure 14, the stresses developed in the stent and the diseased artery were similar, in terms of distribution, for the two cases (with and without residual stresses). In terms of magnitude, the maximum stress in the stent changed only by ~0.7% (928.9 to 935.0 MPa) when residual stresses were included in the simulations. For the diseased artery, the peak value of the maximum principal stress changed by ~5% (1.50 MPa to 1.43 MPa) when the residual stresses were considered.

DISCUSSION

Clinically, in-stent restenosis (ISR), i.e. re-narrowing of stented artery, is one of the major drawbacks associated with stent implantation. [30] ISR is a direct consequence of the formation of neointima, largely caused by proliferating smooth muscle cells and accumulated extracellular matrix. [30] According to recent investigations, arterial wall biomechanics plays a key role in ISR. The stenting-caused alteration of biomechanical environment controls the inflammatory and remodelling processes of vessel walls. As reported by Timmins et al., [31] stent designs that induced higher In-vitro studies have also proved that mechanical stresses regulated the proliferation and migration of vascular cells, [32] and the synthesis and reorganization of extracellular matrix. [33] Stent-induced vessel stresses are closely linked with the level of artery injury, also promoting the development of restenosis. From this study, it is clear that the stresses in the artery appear to be largely affected by the stent materials and designs. PLLA has lower modulus, yield strength and strain hardening, which soothed the stent-artery interaction and led to stress reduction in vessel layers as shown in Figure 10. This is clinically beneficial. Bioresorbable polymeric stents are also more compliant than metallic stents, diminishing associated vascular responses over the scaffolded vessel segments. [34] Residual stresses in stents were studied by Möller et al. [35] using X-ray diffraction method. Their work confirmed that even for as-produced stents, a significant amount of microstresses can be developed in the stent during crimping (this is also the case found in our work). Subsequent stent expansion caused an increase of stress due to tension. According to their study, the level of stresses introduced by crimping and expansion can considerably affect the fatigue life of the stent. Based on our results, crimping and expansion processes were found to induce comparable levels of stresses in the stent struts. Also, residual stresses developed during crimping affected the expansion behaviour, though only slightly, of stent in the deployment step. It is also thought that residual stresses in the stent contributed to the flexibility of the device, thus imposing less stresses on the plaque during further deformation as confirmed by our simulation results, although only marginally.

The targeted vessel diameter (i.e. 3 mm) could not be achieved by stent expansion only. This is the case for both polymer and metallic stents. Firstly, it was due to the saturated expansion of the artery layers, developed at a later stage of vessel stretching. This happened when the stiffness of vessel layers, especially the intima layer, increased steeply upon large stretch [ Figure 4]. Secondly, vessel layers were assumed to deform purely elastically which imposed a large recovery force on the expanded stent after balloon deflation. Generally, the expansion of polymer stent was slower than that of metallic stent. Higher recoiling was also observed for polymeric stent due to the weaker mechanical properties. This indicates that there is a challenge to use polymer stents to achieve desired lumen diameter, especially for patients with stiffer artery and heavily calcified plaques. However, it is recognised that polymer stent induced significantly lower stresses in the artery than metallic stents, which could reduce the occurrence of arterial injuries and instent restenosis.

In clinical practice, most stents are post-dilated with relatively non-compliant balloons, i.e. stiffer and larger than the stent delivery system balloon, to ensure good apposition and to ensure that the intended diameter is achieved. However, multiple cycles of inflation were not simulated here which is a limitation of this study. The simulation in this work was a single deployment of stent or direct stenting of a vascular lesion. In clinical practice, pre-dilatation of diseased artery can also occur. Direct-stenting is common, but not with bioresorbable polymer stents. For bioresorbable polymer stents (or any new technology), the users generally acknowledge the importance of careful lesion preparation by pre-dilatation as well as post-dilatation.

The pre-dilatation balloon inflation step modifies the plaque and results in less recoil after deployment of a stent or scaffold. After a stent is deployed, an additional post-dilatation generally occurs with a second larger balloon. Sometimes this is to achieve a better deployment through a tapered vessel, or to "crack" a stubborn plaque. Sometimes, this is required when two stents are deployed with an overlap. This type of balloon pre-dilatation and post-dilatation is essential for polymer stents to be effective in difficult lesions. In fact, larger degrees of recoil and dogboning predicted by the simulations indicate that adequate pre-dilatation and post-dilatation are potentially critical for polymeric stents to achieve optimal clinical results. Simulation of pre-dilation or post-dilation requires proper inelastic or damage models to describe unrecoverable deformation for the plaque and artery wall, which is currently beyond the scope of the paper. In this study, the artery and plaque were assumed to behave purely elastically (hyperelastic model), and the efforts of pre-dilation or post-dilation will be nullified as soon as the dilation pressure is removed. Modelling of inelastic deformation and damage will be attempted in our future work.

In addition, the stresses in the vessel layers at peak inflating pressure are generally beyond the ultimate tensile strength of the tissue layer. [25] This is also the case for the plaques. Therefore, tissue damage will need to be modelled in the FE simulations at high pressure levels. Tissue damage is associated with unrecoverable deformation in the artery, which could reduce the stent recoiling considerably upon balloon deflation. Consequently, stent is expected to expand further if tissue damage is considered due to irrecoverable mechanical deformation of the arteryplaque system, thus resulting in a larger lumen diameter. Damage modeling of arterial layers is a limitation of this study and will be studied in our future work. However, it does not affect the general conclusion of this paper, as we aim to make like-for-like comparison of the scaffolding capability and mechanical performance between bioresorbable polymeric and metallic stents.

On the other hand, the plaque can be classified as hypocellular, cellular or calcified, depending on the composition. It is more difficult to treat calcified plaque by stenting due to its strong resistance to stretch when compared to hypocellular or cellular plaques. [18] So far, the effect of plaque composition on stent expansion was only evaluated for isotropic tissue model, and further work is required to study such effects by considering vessel anisotropy. Finally, polymers generally possess anisotropy and viscoplasticity effects which could also affect the simulation results and will need to be addressed in future studies.

In conclusion, crimping and deployment of polymeric and metallic stents have been simulated using finite element method to give a direct comparison of their mechanical performances. Results demonstrated that polymer stent has a lower rate of expansion than metallic stent. The overall expansion, reached at peak inflating pressure and after balloon deflation, was lower for polymer stent due to weaker material properties. This is also associated with the higher recoiling effect for polymer stent. Thus, it is a challenge to use polymer stent to treat patients with heavily calcified plaques or stiffer vessels, without pre-dilation or post-dilation. Crimping generated severe residual stresses in the stent, which tend to affect stent expansion and increase dogboning for Elixir polymer stent. However, they did not alter the stress distribution during the deployment process, and only imposed small changes to the stress magnitude.

Financial support and sponsorship

icts of interest

There are no conflicts of interest.

Patient consent

There is no patient involved.

Ethics approval

This article does not contain any studies with human participants or animals.

Figure 1 :Figure 2 :Figure 3 :
123Geometry and mesh for (A) Elixir and (B) Xience stents Geometry and mesh of the artery with stenosis and angioplasty balloon Stress-strain curves for the Co-Cr L605 alloy and Poly-L lactide

Figure 4 :
4Stress-stretch curves for the three artery layers: Holzapfel-Gasser-Ogden model vs. experimental data[25]

Figure 5 :Figure 6 :
56Illustration of assembly used in crimping simulation for Elixir stent Deformation of Elixir stent and balloon (A) before, (B) during and (C) at the end of the crimping process local damage to plaque/artery where the high stresses are located. This condition also leads to the growth of new tissue, e.g. proliferation of smooth muscle cells, around the stent, causing in-stent restenosis.

Figure 7 :Figure 8 :
78Von Mises stress (MPa) contour plot for the Elixir (left) and Xience (right) stents in (A) fully crimped state and (B) spring-back state (A) Diameter change against pressure; (B) recoiling and dogboning effects during deployment of Elixir and Xience stents

Figure 9 :Figure 10 :
910Contour plot of the von Mises stress (MPa) on (A) Elixir and (B) Xience stents after deployment Contour plot of maximum principal stress (MPa) on the stenotic plaque after stent deployment: (A) Elixir and (B) Xience stents

Figure 11 :Figure 12 :
1112(A) Diameter change against pressure; and (B) recoiling and dogboning effects obtained from simulations with and without considering crimping-caused post-crimping stresses on Elixir stent (A) von Mises stress (MPa) on the Elixir stent; and (B) maximum principal stress (MPa) on the artery-plaque system for simulations with (left) and without (right) considering residual stresses levels of non-physiologic stresses provoked a more aggressive pathobiological response of the vessel walls, leading to a higher degree of neointimal formation.

Figure 13 :Figure 14 :
1314(A) Diameter change against pressure; and (B) recoiling and dogboning effects obtained from simulations with and without considering crimping-caused residual stresses on Xience stent (A) von Mises stress on the Xience stent; and (B) maximum principal stress on the artery-plaque system for simulation with (left) and without (right) considering residual stresses

Table 1 :
1Properties for the Co-Cr L605 and Poly-L lactide stent materials[20,21] Material
ρ (kg/mm 3 ) E (GPa)
ν
σy (MPa)

Co-Cr L605
9.1E-6
243
0.30
476
Poly-L lactide
1.4E-6
2.2
0.30
60

Table 2 :
2Parameter values of the anisotropic Holzapfel-Gasser-Ogden model for the arterial layersLayer
ρ (kg/mm 3 )
C 10
D
k 1
k 2
k
γ

Intima
1.066E-6
0.03
8.95E-7
4.0
1200.0
0.303
60°M
edia
1.066E-6
0.005
5.31E-6
0.57
80.0
0.313
20°A
dventitia
1.066E-6
8.32E-3
4.67E-6
1.0
1000.0
0.303
67°

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