Cost-effectiveness of corneal collagen cross-linking for keratoconus in district general hospital settings in the United Kingdom

Cost-effectiveness of corneal collagen cross-linking for keratoconus in district general hospital settings in the United Kingdom | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cost-effectiveness of corneal collagen cross-linking for keratoconus in district general hospital settings in the United Kingdom Panagiotis Dervenis, Nikolaos Dervenis, Fook Chang Lam This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4496020/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Keratoconus is a bilateral corneal ectasia occurring in adolescence or early adulthood. Collagen crosslinking is being used as an option to halt disease progression. However, still many district general hospitals lack the equipment of performing this rather straightforward procedure. The aim of this study is to assess how cost-effectiveness of crosslinking when performed in district units compares to crosslinking in tertiary centers. Methods A Markov model was constructed consisting of two different cohorts. One cohort included patients having crosslinking in district units, while the second included patients that were initially examined in district hospitals but then they were referred to tertiary centers in order to have the same treatment. Data for the first cohort were derived from audit data in our department, whereas for the tertiary cohort we used already published data. Sensitivity analyses were performed to examine the robustness of our results. Results In the base case, crosslinking performed in district general hospitals proved to be more effective and less costly compared to crosslinking in tertiary units. Assuming a lifelong efficacy of crosslinking, this leads to an extra cost of £238,782.33/QALY, whereas assuming a 10-year efficacy crosslinking in district general hospitals saves £1,062,962.96/QALY. In any case, crosslinking in district units remains cost effective compared to the NHS willingness-to-pay ratio of £30000/QALY. Decision making is unaffected by the initial disease severity, the proportion of bilateral cases treated and the discount rate of the utilities and the costs. Conclusion Collagen crosslinking when performed in district general hospitals is more effective and less costly for the healthcare system. Coordinated actions should be taken in order to equip even more district units with all the necessary equipment so that patients can be treated locally rather than be referred to tertiary centers. Cornea cost analysis cross-linking keratoconus Figures Figure 1 Figure 2 Figure 3 Introduction Keratoconus has been classically characterized as a degenerative, non-inflammatory corneal ectasia affecting approximately 1 per 2,000 people [1]. It is usually diagnosed during the second and third decades of life. Most patients present bilateral disease at presentation. However, some individuals might show unilateral disease initially. Early disease with conical protrusion of the cornea occurs usually in the adolescence and can last up to the age of 50[2]. The pathophysiology of keratoconus is yet to be determined. However, it is thought to be the result of a combination of biochemical, physical and genetic causes. Ocular associations related to keratoconus have been reported. These include vernal keratoconjunctivitis, retinitis pigmentosa and Leber’s congenital amaurosis. Systemic associations include connective tissue disorders, atopic dermatitis, Down’s syndrome and mitral valve prolapse[1]. Diagnosis is made based on clinical examination and corneal topographic/tomographic findings. Sings include Munson’s sign (an acute protrusion of the cornea in the lower lid on downgaze, epithelial deposition of iron around the base of the cone (Fleischer’s ring) and Vogt’s striae (stress lines in the Descemet’s membrane). Oil droplet sign may be visible on ophthalmoscopy, while scissoring and distortion of the red reflex can be seen on retinoscopy. Corneal topography characteristics include an area of increased corneal power with surrounding concentric areas of decreasing power, inferior-superior power asymmetry and skewing of the steepest axes above and below the horizontal meridian[1]. Epithelial thickness mapping can also help in the diagnosis of early keratoconus[3]. Patients experience corneal stroma thinning that induces irregular astigmatism, myopia and in the advanced stages scarring. Hydrops can also occur due to breaks in the Descemet’s membrane and sudden corneal oedema. This alteration of the shape of the cornea leads to a reduction in the quality of vision and the quality of life[1,4]. Conservative management in the early stages of keratoconus consists of spectacle correction or an attempt to normalize corneal irregularity using rigid gas permeable contact lenses[5]. Various designs and fittings of contact lenses have been developed the address the challenging needs of this condition. Intrastromal rings are small implants that can be inserted into the cornea in an attempt to flatten it and improve visual acuity[1]. However, they do not change the underlying biochemical properties of the cornea. Although the rate of progression is variable, keratoconus can progress quickly in younger patients and patients with steeper maximum curvature power (Kmax) on presentation, thus necessitating further treatment that consists of more interventive measures and even corneal transplantation in about 10–25% of patients[6–8]. Corneal transplantation can be either a full thickness penetrating keratoplasty or deep anterior lamellar keratoplasty[9]. Reduced visual function and the need for corneal graft are linked to a decrease quality of life for the patient[10]. Corneal collagen crosslinking (CXL) is being used the last 20 years as an alternative to halt the progression of keratoconus by increasing the stiffness of the cornea[11]. CXL can be applied either after initially removing the epithelium of the cornea (epithelium off CXL) or without removing the epithelium (epithelium on). By emitting ultraviolet-A light (UVA) in a riboflavin soaked cornea, covalent bonds are being formed between adjacent stromal collagen fibrils[12]. Different protocols have been developed, altering the duration of the UVA radiation and the power of the UVA radiation. CXL has been reported to both stop the progression of keratoconus and slightly improve visual function[13–15]. Moreover, CXL can lead to a reduced risk of corneal transplantation[16]. National institute for health and care excellence guidance recommends the use of CXL for the treatment of keratoconus in the NHS for more than 10 years now[17]. However, generally speaking, organized CXL services are missing from many district general hospitals (DGH) and remain a privilege of the tertiary centers. This can consist a treatment burden for patients with progressive keratoconus. In this study we present the results of our simulation model comparing the cost effectiveness of CXL in DGH settings to tertiary hospitals from an NHS service provider perspective. Materials and methods Model and population We built a Markov model using Microsoft Excel 2016 (Microsoft, Redmond, WA) consisting of two identical cohorts. Each cohort contained 1000 virtual patients who were treated with CXL for bilateral progressive keratoconus (2000 eyes in each cohort). Both cohorts were diagnosed with bilateral progressive keratoconus in DGH facilities, and then one was treated with CXL in the same hospital (DGH cohort) while the other was referred to the tertiary center for CXL treatment (Tertiary cohort). The clinical characteristics of each cohort were based on patient data obtained from previously published studies for progressive keratoconus [13,15]. Patients were categorized into three distinct best corrected visual acuity (BCVA) categories in order to represent disease severity: good, visual acuity (VA) of 0.3 logarithm of the minimum angle of resolution (logMAR) or less (60%), medium, VA of 0.3 to 0.6 logMAR (35%) and bad VA 0.6 logMAR or more (5%). Our decision to use these three categories was based on previously published relationship between utilities and VA [10]. In our study, all patients entered the model at the age of 20. The model had a 30 years horizon, since it has been reported that keratoconus stabilizes after the age of 50 in most of the cases, and 1-year cycle length [2]. Every patient had an individual risk of disease progression and every eye of each patient had an individual probability of disease progression. In the DGH cohort, the probabilities for disease progression to a different BCVA category were obtained from audit data from our center including 136 patients, whereas for the Tertiary cohort data were obtained from already published observational studies of keratoconus in tertiary centres [13]. We ran the model assuming either lifelong efficacy of CXL or a 10-year efficacy of CXL in stabilizing the cornea. We didn’t model retreatment effect in our cohorts because it has been reported that repeated CXL does not provide additional stiffening of the corneas [18]. Moreover, it has been postulated that treatment delay for the keratoconus patients can cause further reduction in vision and progression of the disease [19]. However, for modeling purposes, we assume that the potential delay in treating the patients in the Tertiary cohort has no impact in the outcome. This assumption is in accordance with the Markovian assumption which states that the probability of transitioning between states does not take into account history or how long a subject has been in the current state. Figure 1 shows the transition of patients between VA groups. The probabilities for progressing to a different treatment group are shown in Table 1 . Table 1 Probabilities of progression to different treatment groups. Cohort Baseline VA Change to Probability DGH Good Good 0.90 Good Medium 0.10 Good Bad 0 Medium Good 0.77 Medium Medium 0.20 Medium Bad 0.03 Bad Good 0.18 Bad Medium 0.58 Bad Bad 0.24 Tertiary Good Good 0.92 Good Medium 0.08 Good Bad 0 Medium Good 0.72 Medium Medium 0.14 Medium Bad 0.14 Bad Good 0.20 Bad Medium 0.60 Bad Bad 0.20 Utilities and costs Every particular health state is given a value between 0 and 1, according to the expected quality of life in that state [20]. Quality of life has been reported to be correlated to the visual acuity of the better seeing eye [21]. In our model, utility values were calculated for each patient separately according to the better seeing eye, using data published for the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) cohort (Table 2 ) [10]. Table 2 Utility values based on better seeing eye. VA stage QALY (better seeing eye) Good 0.85 Medium 0.83 Bad 0.81 We didn’t model separately the effect of adverse events and complications on the utility values, since they have already been incorporated in the CLEK cohort. Treatment and monitoring costs in the model were derived from the NHS National Tariff 2022-23 and from the official catalogues of companies trading ophthalmology products (Table 3 ). Table 3 Treatment and monitoring costs. Description of cost DGH costs analysis Tertiary referral costs analysis Source Collagen crosslinking treatment Procedure: £212 Procedure: £212 NICE OPCS 51.8 Riboflavin (1 ml solution): £75 Riboflavin (1 ml solution): £75 Kestrel Ophthalmics Ltd Outpatient visits: £142 the first visit and 3 x £64 each subsequent follow-up visit Outpatient visits: 1 x £142 the first visit in DGH, 1 x £142 the first visit in Tertiary and 3 x £64 each subsequent postoperative follow-up visit NHS National Tariff 2022–2023 Two keratometry measurements: £145 each Three keratometry measurements (1 in DGH and 2 in tertiary hospital): £145 each HRG BZ13 Follow-up medication for 1 month: £35 Follow-up medication for 1 month: £35 BNF Total costs £946 £1233 A 3.5% yearly discount was applied to both utilities and costs, based on the National Institute for Health and Care Excellence (NICE) guidelines [22]. Results Visual acuity state In both groups, 60% of patients started with good VA, 35% of patients started with medium VA and 5% of patients started with bad VA. Assuming a lifelong efficacy of CXL in halting keratoconus progression, after 10 years in the DGH cohort, 87.4% of patients had good VA, 12.1% of patients had medium VA and 0.5% of patients had bad VA, whereas in the tertiary cohort the proportions were 88.4%, 9.5% and 2.1% respectively. After 30 years, in the DGH cohort 88.6% of patients had good VA, 11.1% of patients had medium VA and 0.3% of patients had bad VA, whereas in the tertiary cohort 89.7% of patients had good VA, 8.3% had medium VA and 2% had bad VA. Assuming a 10-year efficacy of CXL in halting keratoconus progression, 73.1% of patients in the DGH cohort had good VA, 12.7% of patients had medium VA and 14.2% of patients had bad VA. In the tertiary cohort 73.3% of patients had good VA, 11.1% of patients had medium VA and 15.6% of patients had bad VA. Quality adjusted life years (QALY) and healthcare costs After 30 years and assuming a lifelong efficacy of CXL in halting keratoconus progression, QALYs of patients in the DGH cohort were 31741.92, while treatment costed £1.89 million. On the other hand, QALYs of patients in the tertiary cohort were 31734.53, while treatment cost was £2.46 million (ICER= -82000/QALY < 0). Assuming a 10-year efficacy of CXL in halting keratoconus progression, QALYs were equal to 22085.78 in the DGH and 19243.23 in the tertiary hospital. Therefore, it is evident that providing CXL in DGH settings is at least as effective as treating patients exclusively in tertiary hospitals. Cost effectiveness Assuming a lifelong efficacy of corneal cross linking in halting keratoconus progression, the incremental cost-effectiveness ratio (ICER) for progressive bilateral keratoconus is £-77672.53/QALY < 0. Assuming a 10-year efficacy of CXL for progressive keratoconus, ICER is £-201.93/QALY < 0. Thus, availability of CXL in DGH is far more cost effective, leading to saving money for at least the same efficacy. Cost effectiveness planes for both scenarios are presented in Fig. 2 . When comparing our results with NHS willingness-to-pay rates (£20000 to £30000 per QALY gained), it is obvious that CXL in DGH remains a cost effective alternative [22]. Sensitivity analyses Sensitivity analyses were performed in order to assess the effect of different variables on the results. Although our analysis remains robust after any sensitivity analysis performed, duration of treatment efficacy has the largest effect on the results. Results of all sensitivity analyses are shown in a Tornado plot (Fig. 3 ). Discussion Progression of keratoconus can severely affect not only patients’ vision but also their quality of life[23]. Therefore, it is necessary to offer treatment to patients in a timely manner. This is very important in these patients since visual acuity cannot be easily improved with glasses or contact lenses, thus necessitating corneal transplantation. Risk factors for progression include a higher Kmax reading at presentation and history of atopy. Thus, CXL should be widely available in all eye units to facilitate prompt treatment of those in need. CXL has been reported to be cost effective for the management of progressive keratoconus in the United Kingdom[24]. Our analysis shows that CXL performed in DGH setting is at least as efficient as it is when performed in tertiary centers. Assuming a 10-year efficacy of CXL, our analysis showed that £201.93/QALY of healthcare cost can be saved if the whole management of a keratoconus patients is performed in the DGH, whereas for a lifelong efficacy of CXL, this amount can rise to £77672.53. However, it has been reported that CXL treatment offers continued improvement even in the long term for keratoconus patients [14]. As a result, it is logical to assume that offering CXL in as many DGH as possible will provide even further savings. Moreover, our base analysis was robust to all further sensitivity analyses, including disease severity when presenting, proportion of bilateral eyes treated, and discount rates. Our study has some considerable strengths. To begin with, it was performed from a healthcare provider perspective, not including other costs outside the healthcare system like travel, loss of productivity, etc. Secondly, we did not take into account the possible progression of keratoconus resulted by the backlog and the long waiting lists possibly caused when referring all patients to only few tertiary centers, which was dramatically affected as well by the recent pandemic [19]. This was done in order to keep the assumptions number to a minimum, and only get the most conservative results. If we had incorporated all of the above, it is obvious that the results would have been more favorable towards offering CXL in DGH settings. On the other hand, our analysis also has few limitations. Firstly, in our model we made the assumption that all the patients were offered treatment on the basis of documented disease progression. If the criteria for treatment were less strict (e.g. treatment offered without obvious disease progression), then probably the cost benefit would have been smaller. On the contrary, if we only treated patients with high risk of disease progression, cost benefit would have been greater. Secondly, we have not included any complication in our model, because, although they are quite rare, they have already been included in the CLEK cohort. Moreover, data for our analysis were acquired only from our audit data in our department and may not mirror the efficacy of CXL in all the hospitals. To the best of our knowledge, this is the first report comparing the cost-effectiveness of CXL in DGH settings to CXL in tertiary hospitals. It clearly demonstrates that CXL offered in DGH as well can dramatically reduce the resources needed for the healthcare system. Therefore, we anticipate that our findings will be very interesting both for clinicians working with keratoconus patients, but also for the healthcare system, by changing the approach of how keratoconus patients are managed. Conclusion We believe that the results of our study clearly demonstrate that offering CXL in DGH settings is a superior alternative to only offer it in a few tertiary centers. Collagen crosslinking offered in DGH for patients initially presented there can help the healthcare system save a maximum of £77672.53/QALY when assuming long-term efficacy. It is also well within the NHS willingness-to-pay rates. As a result, it is clear that a decentralization of care for patients with keratoconus needing crosslinking is needed. Declarations Funding: The authors declare that no funds, grants or other support were received during the preparation of this manuscript. Competing interests: The authors have no relevant financial or non-financial interests to disclose. Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Panagiotis Dervenis. The first draft of the manuscript was written by PD, ND and FCL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Rabinowitz, Y.S. Keratoconus. Surv Ophthalmol 1998 , 42 , 297-319, doi:10.1016/s0039-6257(97)00119-7. Millodot, M.; Ortenberg, I.; Lahav-Yacouel, K.; Behrman, S. Effect of ageing on keratoconic corneas. J Optom 2016 , 9 , 72-77, doi:10.1016/j.optom.2015.05.001. 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Eye (Lond) 2015 , 29 , 1504-1511, doi:10.1038/eye.2015.151. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4496020","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":313240000,"identity":"d34a0106-d135-48cd-a903-83b026893877","order_by":0,"name":"Panagiotis Dervenis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABKUlEQVRIiWNgGAWjYNACAwYGNjDJAGIwHwBSEjKEtEggaWFLAGnhIWSPBANMCwMDD5iBU4s5+9mDH78U2NTx8R/e+LiyzSaPj//M51c3aix4GNgPH92ARYtlT16ytIxBmgSbRFqx4dm2tGI2idxt1jnHgA7jSUu7gc0XB3IMpCUMDgO18JhJNpw5nNgmwbvNOAfIBXrHDKuW82+Mf4O18J8x/9lw5n9iG/+ZZ8Y5//BouZFjJvkBpIUhx4yxoeJAYhtDDvPj3DbcWixnvDGzZjBIk2wD+kWyoSIZ6LA0M+bcPgkeNhx+MefPMb75448Nv3z/4Y0fGwzsEuf3H378OedbnRw/++FjWB0GxMzoUcAmASaxKIdpYfyBJsj8AYfqUTAKRsEoGJkAALqnXCDS7h68AAAAAElFTkSuQmCC","orcid":"","institution":"Western Sussex Eye Care, University Hospitals Sussex NHS Foundation Trust","correspondingAuthor":true,"prefix":"","firstName":"Panagiotis","middleName":"","lastName":"Dervenis","suffix":""},{"id":313240001,"identity":"1b07b3bb-3869-435f-93d9-d6a8971e0a6e","order_by":1,"name":"Nikolaos Dervenis","email":"","orcid":"","institution":"University of Liverpool","correspondingAuthor":false,"prefix":"","firstName":"Nikolaos","middleName":"","lastName":"Dervenis","suffix":""},{"id":313240002,"identity":"a024da88-183e-447b-aaad-9e0606482955","order_by":2,"name":"Fook Chang Lam","email":"","orcid":"","institution":"Western Sussex Eye Care, University Hospitals Sussex NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Fook","middleName":"Chang","lastName":"Lam","suffix":""}],"badges":[],"createdAt":"2024-05-29 09:41:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4496020/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4496020/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58308008,"identity":"552f6683-8eac-41fc-b63f-c0aabe0d8d47","added_by":"auto","created_at":"2024-06-13 18:45:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46727,"visible":true,"origin":"","legend":"\u003cp\u003eTransition of patients between different visual acuity groups.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4496020/v1/1dac7b746b2fc81fd886f147.jpg"},{"id":58308009,"identity":"1439a3d2-f9d1-46b8-b622-4bf26ef98002","added_by":"auto","created_at":"2024-06-13 18:45:38","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26456,"visible":true,"origin":"","legend":"\u003cp\u003eCost effectiveness planes of DGH and Tertiary models.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4496020/v1/74e8af29e31903a8aed358a5.jpg"},{"id":58307963,"identity":"7591bb90-78d1-4ffb-abb7-1c9fa19ae085","added_by":"auto","created_at":"2024-06-13 18:45:36","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":21283,"visible":true,"origin":"","legend":"\u003cp\u003eTornado plot of sensitivity analyses\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4496020/v1/0ff3cbb1a75bd832f858aa23.jpg"},{"id":70449595,"identity":"1ab3ccbb-3931-4e7e-a5c6-2bbab7721d1e","added_by":"auto","created_at":"2024-12-03 09:25:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":541860,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4496020/v1/17815ef4-2e81-42e0-b0ec-2ccafd505e0b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cost-effectiveness of corneal collagen cross-linking for keratoconus in district general hospital settings in the United Kingdom","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKeratoconus has been classically characterized as a degenerative, non-inflammatory corneal ectasia affecting approximately 1 per 2,000 people [1]. It is usually diagnosed during the second and third decades of life. Most patients present bilateral disease at presentation. However, some individuals might show unilateral disease initially. Early disease with conical protrusion of the cornea occurs usually in the adolescence and can last up to the age of 50[2].\u003c/p\u003e \u003cp\u003eThe pathophysiology of keratoconus is yet to be determined. However, it is thought to be the result of a combination of biochemical, physical and genetic causes. Ocular associations related to keratoconus have been reported. These include vernal keratoconjunctivitis, retinitis pigmentosa and Leber\u0026rsquo;s congenital amaurosis. Systemic associations include connective tissue disorders, atopic dermatitis, Down\u0026rsquo;s syndrome and mitral valve prolapse[1].\u003c/p\u003e \u003cp\u003eDiagnosis is made based on clinical examination and corneal topographic/tomographic findings. Sings include Munson\u0026rsquo;s sign (an acute protrusion of the cornea in the lower lid on downgaze, epithelial deposition of iron around the base of the cone (Fleischer\u0026rsquo;s ring) and Vogt\u0026rsquo;s striae (stress lines in the Descemet\u0026rsquo;s membrane). Oil droplet sign may be visible on ophthalmoscopy, while scissoring and distortion of the red reflex can be seen on retinoscopy. Corneal topography characteristics include an area of increased corneal power with surrounding concentric areas of decreasing power, inferior-superior power asymmetry and skewing of the steepest axes above and below the horizontal meridian[1]. Epithelial thickness mapping can also help in the diagnosis of early keratoconus[3].\u003c/p\u003e \u003cp\u003ePatients experience corneal stroma thinning that induces irregular astigmatism, myopia and in the advanced stages scarring. Hydrops can also occur due to breaks in the Descemet\u0026rsquo;s membrane and sudden corneal oedema. This alteration of the shape of the cornea leads to a reduction in the quality of vision and the quality of life[1,4]. Conservative management in the early stages of keratoconus consists of spectacle correction or an attempt to normalize corneal irregularity using rigid gas permeable contact lenses[5]. Various designs and fittings of contact lenses have been developed the address the challenging needs of this condition. Intrastromal rings are small implants that can be inserted into the cornea in an attempt to flatten it and improve visual acuity[1]. However, they do not change the underlying biochemical properties of the cornea. Although the rate of progression is variable, keratoconus can progress quickly in younger patients and patients with steeper maximum curvature power (Kmax) on presentation, thus necessitating further treatment that consists of more interventive measures and even corneal transplantation in about 10\u0026ndash;25% of patients[6\u0026ndash;8]. Corneal transplantation can be either a full thickness penetrating keratoplasty or deep anterior lamellar keratoplasty[9]. Reduced visual function and the need for corneal graft are linked to a decrease quality of life for the patient[10].\u003c/p\u003e \u003cp\u003eCorneal collagen crosslinking (CXL) is being used the last 20 years as an alternative to halt the progression of keratoconus by increasing the stiffness of the cornea[11]. CXL can be applied either after initially removing the epithelium of the cornea (epithelium off CXL) or without removing the epithelium (epithelium on). By emitting ultraviolet-A light (UVA) in a riboflavin soaked cornea, covalent bonds are being formed between adjacent stromal collagen fibrils[12]. Different protocols have been developed, altering the duration of the UVA radiation and the power of the UVA radiation. CXL has been reported to both stop the progression of keratoconus and slightly improve visual function[13\u0026ndash;15]. Moreover, CXL can lead to a reduced risk of corneal transplantation[16].\u003c/p\u003e \u003cp\u003e National institute for health and care excellence guidance recommends the use of CXL for the treatment of keratoconus in the NHS for more than 10 years now[17]. However, generally speaking, organized CXL services are missing from many district general hospitals (DGH) and remain a privilege of the tertiary centers. This can consist a treatment burden for patients with progressive keratoconus. In this study we present the results of our simulation model comparing the cost effectiveness of CXL in DGH settings to tertiary hospitals from an NHS service provider perspective.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eModel and population\u003c/h2\u003e \u003cp\u003eWe built a Markov model using Microsoft Excel 2016 (Microsoft, Redmond, WA) consisting of two identical cohorts. Each cohort contained 1000 virtual patients who were treated with CXL for bilateral progressive keratoconus (2000 eyes in each cohort). Both cohorts were diagnosed with bilateral progressive keratoconus in DGH facilities, and then one was treated with CXL in the same hospital (DGH cohort) while the other was referred to the tertiary center for CXL treatment (Tertiary cohort). The clinical characteristics of each cohort were based on patient data obtained from previously published studies for progressive keratoconus [13,15]. Patients were categorized into three distinct best corrected visual acuity (BCVA) categories in order to represent disease severity: good, visual acuity (VA) of 0.3 logarithm of the minimum angle of resolution (logMAR) or less (60%), medium, VA of 0.3 to 0.6 logMAR (35%) and bad VA 0.6 logMAR or more (5%). Our decision to use these three categories was based on previously published relationship between utilities and VA [10].\u003c/p\u003e \u003cp\u003eIn our study, all patients entered the model at the age of 20. The model had a 30 years horizon, since it has been reported that keratoconus stabilizes after the age of 50 in most of the cases, and 1-year cycle length [2]. Every patient had an individual risk of disease progression and every eye of each patient had an individual probability of disease progression. In the DGH cohort, the probabilities for disease progression to a different BCVA category were obtained from audit data from our center including 136 patients, whereas for the Tertiary cohort data were obtained from already published observational studies of keratoconus in tertiary centres [13]. We ran the model assuming either lifelong efficacy of CXL or a 10-year efficacy of CXL in stabilizing the cornea. We didn\u0026rsquo;t model retreatment effect in our cohorts because it has been reported that repeated CXL does not provide additional stiffening of the corneas [18]. Moreover, it has been postulated that treatment delay for the keratoconus patients can cause further reduction in vision and progression of the disease [19]. However, for modeling purposes, we assume that the potential delay in treating the patients in the Tertiary cohort has no impact in the outcome. This assumption is in accordance with the Markovian assumption which states that the probability of transitioning between states does not take into account history or how long a subject has been in the current state. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the transition of patients between VA groups. The probabilities for progressing to a different treatment group are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eProbabilities of progression to different treatment groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCohort\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline VA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChange to\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProbability\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"8\" rowspan=\"9\"\u003e \u003cp\u003eDGH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"8\" rowspan=\"9\"\u003e \u003cp\u003eTertiary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eUtilities and costs\u003c/h2\u003e \u003cp\u003eEvery particular health state is given a value between 0 and 1, according to the expected quality of life in that state [20]. Quality of life has been reported to be correlated to the visual acuity of the better seeing eye [21]. In our model, utility values were calculated for each patient separately according to the better seeing eye, using data published for the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) cohort (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) [10].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUtility values based on better seeing eye.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVA stage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQALY (better seeing eye)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBad\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe didn\u0026rsquo;t model separately the effect of adverse events and complications on the utility values, since they have already been incorporated in the CLEK cohort.\u003c/p\u003e \u003cp\u003eTreatment and monitoring costs in the model were derived from the NHS National Tariff 2022-23 and from the official catalogues of companies trading ophthalmology products (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTreatment and monitoring costs.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDescription of cost\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDGH costs analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTertiary referral costs analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSource\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCollagen crosslinking treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProcedure: \u0026pound;212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProcedure: \u0026pound;212\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNICE OPCS 51.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRiboflavin (1 ml solution): \u0026pound;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRiboflavin (1 ml solution): \u0026pound;75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKestrel Ophthalmics Ltd\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutpatient visits: \u0026pound;142 the first visit and 3 x \u0026pound;64 each subsequent follow-up visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOutpatient visits: 1 x \u0026pound;142 the first visit in DGH, 1 x \u0026pound;142 the first visit in Tertiary and 3 x \u0026pound;64 each subsequent postoperative follow-up visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNHS National Tariff 2022\u0026ndash;2023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTwo keratometry measurements: \u0026pound;145 each\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThree keratometry measurements (1 in DGH and 2 in tertiary hospital): \u0026pound;145 each\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHRG BZ13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFollow-up medication for 1 month: \u0026pound;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFollow-up medication for 1 month: \u0026pound;35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBNF\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal costs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026pound;946\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026pound;1233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e A 3.5% yearly discount was applied to both utilities and costs, based on the National Institute for Health and Care Excellence (NICE) guidelines [22].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eVisual acuity state\u003c/h2\u003e \u003cp\u003eIn both groups, 60% of patients started with good VA, 35% of patients started with medium VA and 5% of patients started with bad VA. Assuming a lifelong efficacy of CXL in halting keratoconus progression, after 10 years in the DGH cohort, 87.4% of patients had good VA, 12.1% of patients had medium VA and 0.5% of patients had bad VA, whereas in the tertiary cohort the proportions were 88.4%, 9.5% and 2.1% respectively. After 30 years, in the DGH cohort 88.6% of patients had good VA, 11.1% of patients had medium VA and 0.3% of patients had bad VA, whereas in the tertiary cohort 89.7% of patients had good VA, 8.3% had medium VA and 2% had bad VA.\u003c/p\u003e \u003cp\u003eAssuming a 10-year efficacy of CXL in halting keratoconus progression, 73.1% of patients in the DGH cohort had good VA, 12.7% of patients had medium VA and 14.2% of patients had bad VA. In the tertiary cohort 73.3% of patients had good VA, 11.1% of patients had medium VA and 15.6% of patients had bad VA.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eQuality adjusted life years (QALY) and healthcare costs\u003c/h2\u003e \u003cp\u003eAfter 30 years and assuming a lifelong efficacy of CXL in halting keratoconus progression, QALYs of patients in the DGH cohort were 31741.92, while treatment costed \u0026pound;1.89\u0026nbsp;million. On the other hand, QALYs of patients in the tertiary cohort were 31734.53, while treatment cost was \u0026pound;2.46\u0026nbsp;million (ICER= -82000/QALY\u0026thinsp;\u0026lt;\u0026thinsp;0).\u003c/p\u003e \u003cp\u003eAssuming a 10-year efficacy of CXL in halting keratoconus progression, QALYs were equal to 22085.78 in the DGH and 19243.23 in the tertiary hospital.\u003c/p\u003e \u003cp\u003eTherefore, it is evident that providing CXL in DGH settings is at least as effective as treating patients exclusively in tertiary hospitals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCost effectiveness\u003c/h2\u003e \u003cp\u003eAssuming a lifelong efficacy of corneal cross linking in halting keratoconus progression, the incremental cost-effectiveness ratio (ICER) for progressive bilateral keratoconus is \u0026pound;-77672.53/QALY\u0026thinsp;\u0026lt;\u0026thinsp;0. Assuming a 10-year efficacy of CXL for progressive keratoconus, ICER is \u0026pound;-201.93/QALY\u0026thinsp;\u0026lt;\u0026thinsp;0.\u003c/p\u003e \u003cp\u003eThus, availability of CXL in DGH is far more cost effective, leading to saving money for at least the same efficacy. Cost effectiveness planes for both scenarios are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhen comparing our results with NHS willingness-to-pay rates (\u0026pound;20000 to \u0026pound;30000 per QALY gained), it is obvious that CXL in DGH remains a cost effective alternative [22].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analyses\u003c/h2\u003e \u003cp\u003eSensitivity analyses were performed in order to assess the effect of different variables on the results. Although our analysis remains robust after any sensitivity analysis performed, duration of treatment efficacy has the largest effect on the results. Results of all sensitivity analyses are shown in a Tornado plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eProgression of keratoconus can severely affect not only patients\u0026rsquo; vision but also their quality of life[23]. Therefore, it is necessary to offer treatment to patients in a timely manner. This is very important in these patients since visual acuity cannot be easily improved with glasses or contact lenses, thus necessitating corneal transplantation. Risk factors for progression include a higher Kmax reading at presentation and history of atopy. Thus, CXL should be widely available in all eye units to facilitate prompt treatment of those in need.\u003c/p\u003e \u003cp\u003eCXL has been reported to be cost effective for the management of progressive keratoconus in the United Kingdom[24]. Our analysis shows that CXL performed in DGH setting is at least as efficient as it is when performed in tertiary centers. Assuming a 10-year efficacy of CXL, our analysis showed that \u0026pound;201.93/QALY of healthcare cost can be saved if the whole management of a keratoconus patients is performed in the DGH, whereas for a lifelong efficacy of CXL, this amount can rise to \u0026pound;77672.53. However, it has been reported that CXL treatment offers continued improvement even in the long term for keratoconus patients [14]. As a result, it is logical to assume that offering CXL in as many DGH as possible will provide even further savings. Moreover, our base analysis was robust to all further sensitivity analyses, including disease severity when presenting, proportion of bilateral eyes treated, and discount rates.\u003c/p\u003e \u003cp\u003eOur study has some considerable strengths. To begin with, it was performed from a healthcare provider perspective, not including other costs outside the healthcare system like travel, loss of productivity, etc. Secondly, we did not take into account the possible progression of keratoconus resulted by the backlog and the long waiting lists possibly caused when referring all patients to only few tertiary centers, which was dramatically affected as well by the recent pandemic [19]. This was done in order to keep the assumptions number to a minimum, and only get the most conservative results. If we had incorporated all of the above, it is obvious that the results would have been more favorable towards offering CXL in DGH settings.\u003c/p\u003e \u003cp\u003eOn the other hand, our analysis also has few limitations. Firstly, in our model we made the assumption that all the patients were offered treatment on the basis of documented disease progression. If the criteria for treatment were less strict (e.g. treatment offered without obvious disease progression), then probably the cost benefit would have been smaller. On the contrary, if we only treated patients with high risk of disease progression, cost benefit would have been greater. Secondly, we have not included any complication in our model, because, although they are quite rare, they have already been included in the CLEK cohort. Moreover, data for our analysis were acquired only from our audit data in our department and may not mirror the efficacy of CXL in all the hospitals.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this is the first report comparing the cost-effectiveness of CXL in DGH settings to CXL in tertiary hospitals. It clearly demonstrates that CXL offered in DGH as well can dramatically reduce the resources needed for the healthcare system. Therefore, we anticipate that our findings will be very interesting both for clinicians working with keratoconus patients, but also for the healthcare system, by changing the approach of how keratoconus patients are managed.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe believe that the results of our study clearly demonstrate that offering CXL in DGH settings is a superior alternative to only offer it in a few tertiary centers. Collagen crosslinking offered in DGH for patients initially presented there can help the healthcare system save a maximum of \u0026pound;77672.53/QALY when assuming long-term efficacy. It is also well within the NHS willingness-to-pay rates. As a result, it is clear that a decentralization of care for patients with keratoconus needing crosslinking is needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThe authors declare that no funds, grants or other support were received during the preparation of this manuscript.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests:\u003c/strong\u003e \u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Panagiotis Dervenis. The first draft of the manuscript was written by PD, ND and FCL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRabinowitz, Y.S. Keratoconus. \u003cem\u003eSurv Ophthalmol \u003c/em\u003e\u003cstrong\u003e1998\u003c/strong\u003e, \u003cem\u003e42\u003c/em\u003e, 297-319, doi:10.1016/s0039-6257(97)00119-7.\u003c/li\u003e\n\u003cli\u003eMillodot, M.; Ortenberg, I.; Lahav-Yacouel, K.; Behrman, S. Effect of ageing on keratoconic corneas. \u003cem\u003eJ Optom \u003c/em\u003e\u003cstrong\u003e2016\u003c/strong\u003e, \u003cem\u003e9\u003c/em\u003e, 72-77, doi:10.1016/j.optom.2015.05.001.\u003c/li\u003e\n\u003cli\u003eReinstein, D.Z.; Gobbe, M.; Archer, T.J.; Silverman, R.H.; Coleman, D.J. Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with artemis very-high frequency digital ultrasound. \u003cem\u003eJ Refract Surg \u003c/em\u003e\u003cstrong\u003e2010\u003c/strong\u003e, \u003cem\u003e26\u003c/em\u003e, 259-271, doi:10.3928/1081597X-20100218-01.\u003c/li\u003e\n\u003cli\u003eKymes, S.M.; Walline, J.J.; Zadnik, K.; Sterling, J.; Gordon, M.O.; Collaborative Longitudinal Evaluation of Keratoconus Study, G. Changes in the quality-of-life of people with keratoconus. \u003cem\u003eAm J Ophthalmol \u003c/em\u003e\u003cstrong\u003e2008\u003c/strong\u003e, \u003cem\u003e145\u003c/em\u003e, 611-617, doi:10.1016/j.ajo.2007.11.017.\u003c/li\u003e\n\u003cli\u003eLim, N.; Vogt, U. 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A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linkage to halt the progression of keratoconus. \u003cem\u003eBr J Ophthalmol \u003c/em\u003e\u003cstrong\u003e2011\u003c/strong\u003e, \u003cem\u003e95\u003c/em\u003e, 1519-1524, doi:10.1136/bjo.2010.196493.\u003c/li\u003e\n\u003cli\u003eRaiskup, F.; Theuring, A.; Pillunat, L.E.; Spoerl, E. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. \u003cem\u003eJ Cataract Refract Surg \u003c/em\u003e\u003cstrong\u003e2015\u003c/strong\u003e, \u003cem\u003e41\u003c/em\u003e, 41-46, doi:10.1016/j.jcrs.2014.09.033.\u003c/li\u003e\n\u003cli\u003eWittig-Silva, C.; Chan, E.; Islam, F.M.; Wu, T.; Whiting, M.; Snibson, G.R. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. \u003cem\u003eOphthalmology \u003c/em\u003e\u003cstrong\u003e2014\u003c/strong\u003e, \u003cem\u003e121\u003c/em\u003e, 812-821, doi:10.1016/j.ophtha.2013.10.028.\u003c/li\u003e\n\u003cli\u003eSandvik, G.F.; Thorsrud, A.; Raen, M.; Ostern, A.E.; Saethre, M.; Drolsum, L. Does Corneal Collagen Cross-linking Reduce the Need for Keratoplasties in Patients With Keratoconus? \u003cem\u003eCornea \u003c/em\u003e\u003cstrong\u003e2015\u003c/strong\u003e, \u003cem\u003e34\u003c/em\u003e, 991-995, doi:10.1097/ICO.0000000000000460.\u003c/li\u003e\n\u003cli\u003eN.I.f.H.a.C.E. Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus and keratectasia. Available online: (accessed on \u003c/li\u003e\n\u003cli\u003eTabibian, D.; Kling, S.; Hammer, A.; Richoz, O.; Hafezi, F. Repeated Cross-linking After a Short Time Does Not Provide Any Additional Biomechanical Stiffness in the Mouse Cornea In Vivo. \u003cem\u003eJ Refract Surg \u003c/em\u003e\u003cstrong\u003e2017\u003c/strong\u003e, \u003cem\u003e33\u003c/em\u003e, 56-60, doi:10.3928/1081597X-20161006-02.\u003c/li\u003e\n\u003cli\u003eShah, H.; Pagano, L.; Vakharia, A.; Coco, G.; Gadhvi, K.A.; Kaye, S.B.; Romano, V. Impact of COVID-19 on keratoconus patients waiting for corneal cross linking. \u003cem\u003eEur J Ophthalmol \u003c/em\u003e\u003cstrong\u003e2021\u003c/strong\u003e, \u003cem\u003e31\u003c/em\u003e, 3490-3493, doi:10.1177/11206721211001315.\u003c/li\u003e\n\u003cli\u003eStevens, K.; Ratcliffe, J. Measuring and valuing health benefits for economic evaluation in adolescence: an assessment of the practicality and validity of the child health utility 9D in the Australian adolescent population. \u003cem\u003eValue Health \u003c/em\u003e\u003cstrong\u003e2012\u003c/strong\u003e, \u003cem\u003e15\u003c/em\u003e, 1092-1099, doi:10.1016/j.jval.2012.07.011.\u003c/li\u003e\n\u003cli\u003eSahebjada, S.; Fenwick, E.K.; Xie, J.; Snibson, G.R.; Daniell, M.D.; Baird, P.N. Impact of keratoconus in the better eye and the worse eye on vision-related quality of life. \u003cem\u003eInvest Ophthalmol Vis Sci \u003c/em\u003e\u003cstrong\u003e2014\u003c/strong\u003e, \u003cem\u003e55\u003c/em\u003e, 412-416, doi:10.1167/iovs.13-12929.\u003c/li\u003e\n\u003cli\u003e(NICE), N.I.f.H.a.C.E. \u003cem\u003eGuide to the Methods of Technology Appraisal\u003c/em\u003e; 2008.\u003c/li\u003e\n\u003cli\u003eSteinberg, J.; Bussmann, N.; Frings, A.; Katz, T.; Druchkiv, V.; Linke, S.J. Quality of life in stable and progressive \u0026apos;early-stage\u0026apos; keratoconus patients. \u003cem\u003eActa Ophthalmol \u003c/em\u003e\u003cstrong\u003e2021\u003c/strong\u003e, \u003cem\u003e99\u003c/em\u003e, e196-e201, doi:10.1111/aos.14564.\u003c/li\u003e\n\u003cli\u003eSalmon, H.A.; Chalk, D.; Stein, K.; Frost, N.A. Cost effectiveness of collagen crosslinking for progressive keratoconus in the UK NHS. \u003cem\u003eEye (Lond) \u003c/em\u003e\u003cstrong\u003e2015\u003c/strong\u003e, \u003cem\u003e29\u003c/em\u003e, 1504-1511, doi:10.1038/eye.2015.151.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cornea, cost analysis, cross-linking, keratoconus","lastPublishedDoi":"10.21203/rs.3.rs-4496020/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4496020/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eKeratoconus is a bilateral corneal ectasia occurring in adolescence or early adulthood. Collagen crosslinking is being used as an option to halt disease progression. However, still many district general hospitals lack the equipment of performing this rather straightforward procedure. The aim of this study is to assess how cost-effectiveness of crosslinking when performed in district units compares to crosslinking in tertiary centers.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA Markov model was constructed consisting of two different cohorts. One cohort included patients having crosslinking in district units, while the second included patients that were initially examined in district hospitals but then they were referred to tertiary centers in order to have the same treatment. Data for the first cohort were derived from audit data in our department, whereas for the tertiary cohort we used already published data. Sensitivity analyses were performed to examine the robustness of our results.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the base case, crosslinking performed in district general hospitals proved to be more effective and less costly compared to crosslinking in tertiary units. Assuming a lifelong efficacy of crosslinking, this leads to an extra cost of \u0026pound;238,782.33/QALY, whereas assuming a 10-year efficacy crosslinking in district general hospitals saves \u0026pound;1,062,962.96/QALY. In any case, crosslinking in district units remains cost effective compared to the NHS willingness-to-pay ratio of \u0026pound;30000/QALY. Decision making is unaffected by the initial disease severity, the proportion of bilateral cases treated and the discount rate of the utilities and the costs.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCollagen crosslinking when performed in district general hospitals is more effective and less costly for the healthcare system. Coordinated actions should be taken in order to equip even more district units with all the necessary equipment so that patients can be treated locally rather than be referred to tertiary centers.\u003c/p\u003e","manuscriptTitle":"Cost-effectiveness of corneal collagen cross-linking for keratoconus in district general hospital settings in the United Kingdom","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-13 18:45:26","doi":"10.21203/rs.3.rs-4496020/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f2db9602-60d9-4f5c-8c0d-1df23469fa5f","owner":[],"postedDate":"June 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-03T09:24:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-13 18:45:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4496020","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4496020","identity":"rs-4496020","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}