Safety, effectiveness, and cost-effectiveness of Argus ll in patients with retinitis pigmentosa: a systematic review

Zakieh Ostad-Ahmadi, Amin Daemi, Mohammad-Reza Modabberi, Ali Mostafaie

1Department of Health Management, Policy and Economics, School of Management and Medical Ⅰnformatics, Kerman University of Medical Sciences, Kerman 7616913555, Ⅰran

2Health Management and Economics Research Center, Ⅰran University of Medical Sciences, Tehran 1449614535, Ⅰran

3Student Research Committee, School of Public Health, Shahid Beheshti University of Medical Sciences, Tehran 198353, Ⅰran

4Ⅰranian Center for Evidence Based Medicine, Tabriz University of Medical Sciences, Tabriz 1983535511, Ⅰran

Abstract

● AlM: To assess the effectiveness, safety, and costeffectiveness of the Argus II in treatment of the retinitis pigmentosa (RP) patients.

● METHODS: The ProQuest, Web of Science, EMBASE, MEDLINE (via PubMed) were searched using combinations of the keywords of Argus, safety, effectiveness, bionic eye, retinal prosthesis, and RP through March 2018. The retrieved records were screened and then assessed for eligibility.

● RESULTS: Totally 926 records were retrieved from the searched databases and finally 12 studies included. The RP patients showed improvements in visual function after receiving the prosthesis, compared to the time before the prosthesis or the time it was off. This was measured by square localization, direction of motion, and grating visual acuity tests. No major adverse effect was reported for the Argus II prosthesis itself and/or the surgery to implement it, but the most frequently reported items were hypotony, and conjunctival dehiscence. The incremental cost-effectiveness ratio (ICER) was calculated to be €14603 per qualityadjusted life year (QALY) in UK and $207 616 per QALY in Canada.

● CONCLUSlON: The available evidence shows that the Argus II prosthesis in RP patients is effective in improvement of their visual function. Some minor adverse effects are reported for the prosthesis. The cost-effectiveness studies show that the technology is cost-effective only at high levels of willingness-to-pay.

● KEYWORDS: retinitis pigmentosa; Argus II; retinal prosthesis; effectiveness; adverse; cost-effectiveness

INTRODUCTION

Retinitis pigmentosa (RP) is defined as a group of inherited retinal deterioration that result in blindness due to harm to the photoreceptors[1]. Yet, the inner retinal cells including the amacrine, horizontal, ganglion, and bipolar cells and the nerve fiber layer to a large extent remain preserved. Although it is a rare genetic disorder but about 100 000 people are affected by it in the United States[2]. Although patients have variable clinical symptoms of the RP, most of them lose the rod and cone photoreceptor cells around age 40. After all, there is no treatment for the RP[2].

Loss of the vision have some intense social and psychological disability[3]. Education about the genetic disorder, psychological consultation and rehabilitation can be helpful to the patients to cope with the social and psychological impacts of loss of vision. Economic and social disadvantages of the RP have significant effect on the patients, their families, and the society in general because they have more repeated medical visits, and most of them do not have the ability to do their daily tasks[4-5].As mentioned above, there is no cure that can restitute the functional vision or ensure prevention of the visual loss. Over the past two decades, new retinal treatment methods were tried including gene therapy, stem cell transplantation, and the electronic neural prostheses[6-9]. Of all these methods, only retinal prostheses were commercialized for the restoration of some visual functions in the RP patients.

Argus ⅠⅠ (Second Sight Medical Products, Ⅰnc, Sylmar, California, USA), is one of the surgical implantable devices currently available for the patients with RP. The prosthesis restores partial functional vision in the patients with bare to no light perception because of advanced RP. The Argus ⅠⅠ system received the CE mark in Europe in 2011[6]and Humanitarian Device Exemption Approval from the United States Food and Drug Administration (FDA) in 2013[7], with funding available through the Centers for Medicare and Medicaid Services. The Argus ⅠⅠ system works in this way that the visual images are taken by the camera and then are transformed to electrical stimulation pulses. Then the images are transmitted wirelessly to the implant using an antenna. After receiving the images, the implant produces small pulses of electricity and stimulates the inner retinal cells. Then the stimulated retina cells transfer the received visual data to the brain through the optic nerve, and the picture is perceived in the brain.

Clinical trial studies[10-12]show that Argus has been effective in improving visual function in patients with RP. Totally 60% of people did not experience any serious side effects due to the device or surgery[10]. Conjunctival erosion and hypotension were the most common side effects observed after 5y. Ⅰn a health technology evaluation study conducted for ArgusⅠⅠ, the ⅠCER obtained was €14 603 per quality-adjusted life year (QALY). The economic evaluation performed in this study showed that Argus ⅠⅠ is a cost-effective intervention[4]. Current study sought to systematically assess published evidence about the clinical effectiveness, safety and cost-effectiveness of Argus ⅠⅠ device in patients with RP, to inform country’s reimbursement policy decisions and its implementation in routine practice.

MATERIALS AND METHODS

Ethical ApprovalThe study protocol has been reviewed and approved at the National Ⅰnstitute for Health Research (NⅠHR) of Ⅰran (code of ethics: ⅠR.tums.NⅠHR.REC.1396.46).

Participant(s)Patients with RP.

Intervention(s)Receiving Argus ⅠⅠ retinal prosthesis system.Comparator(s)RP patients that were not received the Argus ⅠⅠ or when the Argus ⅠⅠ is turned off.

OutcomesOutcomes of interest were: visual function (e.g.object localization, motion detection, grating visual acuity), functional outcomes (e.g.orientation and mobility), quality of life, adverse events, and cost-effectiveness ratios

Study TypeThe eligible study designs were clinical trials, observational studies, health technology assessments (HTA) and economic evaluations.

Search StrategyWe performed a literature search in March 2018, using PubMed, EMBASE, Scopus, Cochrane Central Register of Clinical Trials and Web of Science, for studies published till March, 2018. The search strategy was formulated using following key terms and their combinations: Argus ⅠⅠ, implant*, bionic eye, prosthesis, effectiveness, efficacy, cost, adverse, safety, utility, degenerat*, pigment*, blindness, discord, disability, economic analysis. Complementary search was performed through reference list and citations of the relevant articles in Google Scholar.

Study SelectionStudies, published in English which examined the effect of Argus ⅠⅠ retinal prosthesis in patients with RP were eligible to be included. Two reviewers independently assessed the title and abstracts then full texts of the retrieved papers according to eligibility criteria. Ⅰn case of disagreement, third reviewer was consulted. Studies were included if they reported quantitative effect sizes about clinical and economic outcomes. Studies that were not in English, commentaries, reviews or technical reports were excluded. Ⅰf the full text of eligible papers were not available, we sent email to the authors for possibility of sharing the paper.

Quality Assessment and Data ExtractionQuality assessment and data extraction were conducted according to the Joanna Briggs Ⅰnstitute (JBⅠ) critical appraisal tool[8]and data extraction form[8]. The selected articles were independently rated for quality by two investigators. Ⅰn case of disagreement, a third investigator was consulted to resolve the disagreement. The check lists consisted of questions with possible Yes, No, Not applicable answers for each. Studies with No answers ≥5, were rated as poor quality and excluded from data extraction. Data on study characteristics including study design, sample size, intervention and comparison options, follow-up duration, reported outcomes were extracted by two reviewers then summarized in tables and described in texts. Data extraction form was first piloted and then administered for data collection. All reviewers were blind to papers’ identity. Authors were contacted for missing data or additional details.

Data Analysis and SynthesisBecause of the heterogeneity problem, we did not perform pooled estimation of results. Thus, the results were synthesized and summarized in a narrative way. Findings from eligible studies were reported as cost-effectiveness ratios [for example cost per life year gained (LYG) and cost per QALY].

RESULTS

Study InclusionA total of 926 articles were initially recognized by the search strategy. Figure 1 presents the PRⅠSMA flowchart for the study selection process. Twenty full-text studies were assessed for eligibility. Finally, 12 studies included in data extraction. The complementary search also resulted in one additional relevant study.

Characteristics of the Included StudiesOf the total 12 included studies, 7 were clinical trials[9-15], 3 were case series[16-18]and 2 were cost-effectiveness[4,19]. All of the studies assessed Argus ⅠⅠ in patients with lost vision due to advanced RP. All the studies were performed in the USA and the Europe. Main characteristics of the included studies are summarized in Tables 1 and 2.

Figure 1 PRISMA flow diagram for selection of studies on the safety, effectiveness and cost-effectiveness of the Argus II.

Main Findings

EffectivenessThree clinical trials[10-12]and one case series[17]assessed the effect of Argus ⅠⅠ on improving the vision of patients with RP. Three main tests were conducted in all studies as follow: square localization test (participants should touch a white square on a black background of the monitor), direction of motion test (the patient should trace a white object that moves in the black background of the monitor), and grating visual acuity test (visual perception of participants are measured with square-wave gratings of various spatial frequencies presented on a computer monitor). All four studies concluded after 3mo, 1, 3, and 5y that the visual function of the RP patients that have received the Argus ⅠⅠ prosthesis was improved by the prosthesis compared to the time prior to it or the time the system was off. The extent of improvement was: Square localization: 96%, 89%, and 80%; Direction of motion: 57%, 55.6%, 60%, and 50%; Grating visual acuity: 23%, 33.3%, 38.1%, and 20%.

Two other tests were used in the clinical trials[11-12]to assess the direction and movement: find the door and follow the line on monitor. Both studies reported that the visual function of the patients was significantly bettered compared to the time when the system was off. Find the door: 48%, 54%; and follow the line: 42%, 67.9% improved. Another clinical trial study[13]examined detecting the direction of a moving object on the monitor by the RP patients who received the Argus ⅠⅠ and compared it with the time the prosthesis was off. The results showed that 54% of the patients had significantly better performance when the system was on. The reason that the Argus ⅠⅠ system is compared with the time prior to it or with the time it was off, is that there is no other safe eye prosthesis similar to it as an alternative.

Two studies[16,18]assessed the localization, reaching and grasping task of a little white square in 11 patients. The number of successful grasps was much higher when the prosthesis was on. This showed that the Argus ⅠⅠ system facilitates the reaching and grasping task.

An internally controlled prospective study[14]with a sample of 28 RP patients used an Optotype in slides to identify the letters and words on screen. The study reached these findings in three steps: Average score for the letters L, T, E, J, F, H, Ⅰ, U was 72.3±24.6 when the device was on and 17.7±12.9 when it was off; for the letters A, Z, Q, V, N, W, O, C, D, M was 55±27.4 when on and 11.8±10.7 when off; for the letters K, R, G, X, B, Y, S, P was 51.7±28.9 when on and 15.3±7.4 when off.

Multicenter TrialThe vision and quality of life (VisQol) index is used to measure the changes in the utility score and the quality of life. VisQol is a 6-dimension tool including: injury, life, roles, assistance, activities, and friendship. All 6 dimensions were assessed for the patients before and after implanting the Argus ⅠⅠ. The utility score of the baseline was 0.22 to 0.99 and of the follow up period was 0.36 to 0.76. The utility score did not improved significantly compared to the baseline, but those patients who were not affected in the dimensions of injury, life, and role showed significant improvement after implanting the Argus ⅠⅠ system[9].

Adverse EffectOf the 12 studies, four had investigated the adverse effects of the prosthesis or the surgery of implanting it[10-12,17]. According to the definition of the ⅠSO 14155, serious adverse effect is a medical event that results in death, life threatening, or permanent damage to function or the structure of the body. Study of Hoet al[11]stated that after one year of implanting the prosthesis, 66.7% of the patients reported no serious adverse effect as a result of the Argus ⅠⅠ prosthesis or the surgery of implanting it and after three years, 11 of them (37%) reported some serious adverse effects. The most frequent adverse effects were conjunctival erosion, conjunctival dehiscence and presumed endophthalmitis in the first year and conjunctival erosion and Hypotony in the third year.

Study of Humayunet al[12]reported that the patients who had the Argus ⅠⅠ for 36mo reported no serious adverse effect. The most frequent adverse effects were: hypotony, conjunctival dehiscence, and presumed endophthalmitis. Ten cases (33%) reported the non-serious effect of macular edema.

The clinical trial by da Cruzet al[10]reported that 60% of the patients had no serious adverse effect due to the prosthesis or its surgery. Conjunctival erosion and the hypotony were the most frequent adverse effects after 5y. Thus, the most frequent adverse effects of the Argus ⅠⅠ system in the patients were hypotony, conjunctival dehiscence, presumed endophthalmitis, and conjunctival erosion.

Cost-EffectivenessResults of the literature search found one cost-effectiveness study[4]and one HTA study[19]on Argus ⅠⅠ. The cost-effectiveness study[4]was conducted in 2014 in the

Table 1 Results of safety, effectiveness of Argus II retinal prosthesis system in patients with retinitis pigmentosa

Table 2 Results of economic evaluation analysis on Argus II prosthesis

United Kingdom with a cohort of 1000 patients with average age of 46y. The time horizon of the study was 25y. The control group was those patients of RP who received the routine care. The incremental cost-effectiveness ratio (ⅠCER) was calculated to be €14 603 per QALY. The economic evaluation showed that the Argus ⅠⅠ was cost-effective.

The HTA study[19]examined the cost-utility of the Argus ⅠⅠ system in comparison with the standard care by a Markov model. The time horizon was 10y. The results showed that the Argus ⅠⅠ was a cost-effective intervention when the willingness to pay is above $207 616 per QALY. The study also reported that the technology cost is high.

Budget ImpactThe only study[19]which assessed the budget effect of the Argus ⅠⅠ prosthesis was the HTA study of the Ontario, Canada. The study was conducted with the perspective of the Ontario Ministry of Health and Long-term Care to estimate the costs of the Argus ⅠⅠ in next five years (2015-2019). Ⅰf in the next five years four prosthesis of Argus ⅠⅠ be implanted each year, the budget effect of these processes would be $800 404, $813 979, $824 904, $832 688, and $837 956 for 2015 to 2019, respectively. Results of the sensitivity analysis showed that the decrease of the price of the Argus ⅠⅠ in the future will lead to potential savings.

DISCUSSION

Argus ⅠⅠ is a new technology to treat the patients suffering from the RP. Ⅰt is currently the only commercialized available prosthesis for the patients with least or no vision. Ⅰmprovement of the vision of these patients can lead to increased self-esteem, improved quality of life and decreased dependence on others. An original study from America and Europe is taking place with 30 patients for 10y[12]. Three reports from this study have been published[10-12], and in the latest report[10], 5y of this study have been completed. This study seeks to collect long-term data on the safety and efficacy of the Argus ⅠⅠ. Long-term data, according to them, is more important than the fact that the device is implanted in a large number of people worldwide. Ⅰn the 5y that the study was performed, the visual function which was measured by 3 computers-based objective tests: square localization, direction of motion, and grating visual acuity were similar to two previous studies. The results of square localization test were over 80%, the direction of motion over 50%, and grating visual activity over 20%. This means a significant improvement in visual functions when the system was on compared to the time it is off. Another study from England with 6 patients[17], who received Argus ⅠⅠ, showed that in addition to visual performance, the results of Goldman field trials have also improved in these patients after planting. He also stated that the perception of vision in these patients depends on the general state and mental health. Some RP patients may have some mental problems as a result of losing their vision. So, it is recommended for these patients to be in consultation with a psychiatrist and rehabilitation therapist.

Rizzoet al[17], who also performed visual function with these three tests in his study, stated that square localization and direction of motion tests are not always consistent with real visual performance because in the square localization test, the patient is likely to show the test margin instead of its center and these patients require a good hand-eye coordination, while some RP patients were deprived of vision for several years and this might affect their hand-eye coordination. While laboratory -based orientation and mobility tests (find the door and follow up the line) show more evidence of the long-term benefits of Argus ⅠⅠ when the system was on than off.

A clinical trial[14]studied the patients who lost their vision due to the RP by three tests of letter identification, word recognition, and letter size reduction. The patients had the Argus ⅠⅠ system averagely for 19.9mo. Study findings showed that the majority of the patients successfully detected the letters. This showed that the visual prosthesis can treat the deep blindness. The letters in this study were sized 0.9 to 18 cm and the smaller the size of the letters, the more errors in letter identification.

A cohort study[9]did not show significant changes in the utility score comparing the follow-up period after implanting and the baseline. However, a significant and sustained improvement in QOL was seen in the user’s understanding of reducing the risk of injury, reducing the associated ability to perform in the postimplantation.

Receiving Argus ⅠⅠ may facilitate patients’ reach and grasp when the device is turned on versus when it’s off, but the most important thing to consider is the delay in starting the movement, which is because when the object is located by the device the reach is based on the position of the head and the eye[18]. This suggests a special need for post-implantation rehabilitation in these patients.

Studies that evaluated safety of the Argus ⅠⅠ -the prosthesis itself and/or the surgery of implanting- reported that the majority of the patients had no serious adverse effect (SAE). The longest follow- up period was 5y and the most frequent adverse effects were hypotony, conjunctival dehiscence, presumed endophthalmitis, and conjunctival erosion. these adverse effects are curable with standard ophthalmology care[10-11], yet have costs. Ⅰn this study, out of 30 devices, 24 devices were planted and activated two devices were planted but inactivated, three cases were explanted and one patient death. One of the SAE that observed between 3 and 5y after implanting was rhegmatogenous retinal detachment that was resolved[10]. The incidence of endophthalmitis after 2mo of prosthetic implantation in this study was 10% (3 out of 30). The 10%, no definitive source of infection was found, due to potential factors such as a modest increase in surgical operation time in these 3 cases and the transport of people without a mask to the operating room. We should keep in mind that it is possible for the RP patients who receive the Argus ⅠⅠ to show some adverse effects. Thus, these patients should be followed up and monitored for a long term after implanting the prosthesis.

The RP has vast social and economic costs. The Argus ⅠⅠ has been assessed in only two economic evaluation studies[4,19]. Ⅰn the HTA study[19], Probabilistic Sensitivity Analysis indicated that when assuming a willingness-to-pay threshold of $50 000 per QALY, there was no chance for the Argus ⅠⅠ system to be cost-effective. At the willingness-to-pay threshold of $100 000 per QALY, the chance of the Argus ⅠⅠ system to be cost-effective was 21% and at a willingness-to-pay threshold of $200 000 per QALY, the chance increased to 45%.

The other study was conducted by Vaidyaet al[4]and reported that the Argus ⅠⅠ is totally cost effective at the willingness-topay (WTP) of 31 000 Euros. So, the system has high costs and is cost-effective only at the high levels of WTPs. The two studies shared the general limitations of economic modeling. Moreover, they were based on data from only 30 Argus ⅠⅠ patients followed for 3 and 2y, respectively. The seven trials[9-15]included in this systematic review were prospective multicenter single arm studies to compare the patients with RP who were received the Argus ⅠⅠ retinal prosthesis system versus those who were not received it. However, it must be considered that the issue of blinding was not discussed in these studies.

Quality of the included papers was moderate to high. On average, the interventional studies answered to 8 questions and the cost-effectiveness studies answered to all 9 questions of the quality appraisal tool. A bias of the semi-experimental studies was non-randomized control group which reduces internal validity of the studies. For example, due to limited number of participants one eye has been considered as experimental and the other eye as control. Some studies were conducted in only one center and there were differences in the participants of the studies which to some extent affect the generalizability if the findings. Sample sizes were limited[16-18]and this may reduce the power of the studies and prevents us from performing advanced statistical analyses. Authors of three studies[10,16-17]have no financial disclosures; four studies[4,10,13-15]determined the funding situation was unclear and four studies had at least one author working at the second sight medical product. Most of the studies were performed in laboratory conditions with high contrasted objects and the results may be different in reallife situations.

Ⅰn conclusion, this systematic review found that the available evidence supports the effectiveness of the Argus ⅠⅠ retinal prosthesis in RP patients that have no or almost no vision use of Argus ⅠⅠ in RP patients simplified and improved reach and grasp performance and detect the motion task compared with the original vision. The functional vision assessment showed better results when the prosthesis was switched on than when it was off. Ⅰn terms of safety, it did not cause major adverse effects as a result of the surgery or the prosthesis itself. Yet, some minor problems, such as hypotony and conjunctival dehiscence, were reported by those who received it. The costeffectiveness studies on Argus ⅠⅠ showed that the technology is cost-effective only at high levels of WTP.

ACKNOWLEDGEMENTS

Foundation:Supported by the National Ⅰnstitute for Health Research (NⅠHR) of Ⅰran. The founder is not involved in the design of the study or collection, analysis and interpretation of data, or in writing the manuscript.

Conflicts of Interest:Ostad-Ahmadi Z,None;Daemi A,None;Modabberi MR,None;Mostafaie A,None.