Glaucoma is a substantial public health problem, with a large negative impact on quality of life and the utilization of health care resources. Glaucoma refers to a group of eye conditions with a characteristic pattern of progressive damage to the optic nerve. Raised intraocular pressure (IOP) is the best characterized risk-factor, but IOP can also be normal. Globally, glaucoma is considered the leading cause of irreversible vision loss and one of the leading causes of blindness overall. There are approximately 77,000 Norwegian individuals with a glaucoma diagnosis. The incidence is expected to increase because of demographic changes and because the disease can now be diagnosed at earlier stages than before. Minimally invasive glaucoma surgery (MIGS) represents a class of new surgical procedures and devices to address this issue. Experts suggest MIGS may result in shorter procedure and recovery times than traditional surgical procedures, and that MIGS make it possible to offer treatment at an earlier stage of glaucoma. The indications for each MIGS procedure depend on its mechanism of action and the individual patient’s target IOP and concomitant eye diseases. MIGS procedures and devices can be used alone or in conjunction with cataract surgery. The procedure is already offered in many public hospitals in Norway. Objective The objectives of this health technology assessment (HTA) were to: 1) supplement the evidence of (effectiveness and safety ) of MIGS in an HTA published by the Canadian Agency for Drugs and Technologies in Health (CADTH) in January, 2019, 2) conduct a health economic evaluation of MIGS from a Norwegian health care perspective, and 3) assess organizational and ethical aspects of MIGS in a Norwegian setting.
Clinical effectiveness and safety We have summarized CADTH’s HTA evidence of effectiveness and safety, and adapted CADTH’s methods in the conduct of our supplementary review of more recent studies. CADTH carried out systematic literature searches in August and November 2017, while our updated searches were carried out in August 2019 and November 2020. Searches were run in electronic medical databases, such as MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials, using peer-reviewed search strategies. Two reviewers independently selected studies meeting our inclusion criteria. Likewise, 8 Executive summary two reviewers independently judged the included studies’ risk of bias. One reviewer extracted predefined data, and another reviewer checked the data extraction. The primary outcome in CADTH’s HTA was quality of life, and intraocular pressure in the Norwegian Institute of Public Health (NIPH) HTA supplementary review. When possible, mean differences with 95 % confidence intervals were calculated, and effect estimates were pooled for similar comparisons. When pooling was not possible, findings were reported narratively. One reviewer assessed the certainty of the evidence with the GRADE approach, and a second reviewer checked the assessments.
Health economic evaluation
We based our health economic analysis on the previous HTA carried out by CADTH. We developed six different decision analytic cost-effectiveness models in TreeAge Pro, to estimate incremental cost utility rate (ICER). The models provide insight into costs, health effects, survival, and disease stage. The analysis was carried out from a modified Norwegian health care perspective. We have estimated absolute shortfall for patients with glaucoma. We handled uncertainties in model parameters by assigning probability distributions to the parameters and performing probabilistic sensitivity analysis (PSA), designed as a Monte Carlo simulation. We also performed one-way sensitivity analyses for each of the six models to explore potential impact of uncertainty in single parameters. In addition, we estimated the budget impact of introducing MIGS as a routine treatment option in Norway for patients with glaucoma.
In order to evaluate the organizational consequences related to the implementation of MIGS and a potential increase in volume of MIGS performed in Norwegian hospitals, we asked clinical experts from five of the state-run hospitals that perform MIGS in Norway, to answer a questionnaire regarding their present capacity and procedure used: patient selection, procedures and ongoing trials.
We analysed central ethical implications of MIGS implementation, and the analysis was proceeded in three major steps: First, brief description of the situation, alternative actions and solutions, and the involved stakeholders. Second, analysis of the ethical challenges and possible consequences in terms of the four principles: benefit, harm, autonomy and justice.
Clinical effectiveness and safety
CADTH HTA CADTH’s HTA included 35 publications from 32 studies; 10 randomized trials and 22 non-randomised studies. The evidence included 24 specific comparisons: one comparison of a MIGS versus another MIGS, six comparisons of a MIGS combined with cataract surgery versus cataract surgery alone, nine comparisons of a MIGS combined with cataract surgery versus filtration surgery combined with cataract surgery, six comparisons 9 Executive summary of a MIGS combined with filtration surgery versus filtration surgery alone, two comparisons of a MIGS versus pharmacotherapy, and one comparison of a MIGS versus laser therapy. CADTH’s authors considered all the included studies to have some risk of bias. As shown in the table below with summary of findings by comparison and outcomes (reproduced with kind permission from CADTH), there was largely no statistically significant difference between intervention and comparator and this can be explained because the heterogeneity in interventions and comparisons did not allowed pooling. . The evidence was considered very low or low certainty across comparisons and outcomes.
NIPH supplementary review
We identified and included eight studies (seven randomised trials and one non-randomised study) that compared a MIGS procedure alone or in combination with cataract surgery, with another MIGS procedure or non-MIGS procedures. None of the additional found studies could be pooled with study results in the CADTH HTA. As showed in the summary of findings table below, there was high-certainty evidence of lower IOP with Hydrus in combination with cataract surgery than with cataract surgery alone, and moderate-certainty evidence of lower unmedicated IOP with iStent inject in combination with cataract surgery than with cataract surgery alone. Otherwise, there was no or little difference between the MIGS and interventions in control groups, or the certainty of the evidence was too low to make a judgement. The evidence for the safety of MIGS was inconclusive across the comparisons, but there appeared to be little or no risk of complications associated with any of the treatment options. There also appears to be no standarized method to measure safety. 10 Executive summary Summary of findings: Intraocular pressure (IOP) Effectiveness of MIGS for open-angle glaucoma in adults Patient or population: adults with open-angle glaucoma Intervention: MIGS alone or in combination with other procedure Comparison: other MIGS or other procedure Comparison Anticipated absolute effects* MD (95% CI) № of participants (studies) Certainty of the evidence (GRADE) Comments Intraocular pressure [mm Hg] One MIGS procedure versus another MIGS procedure Hydrus vs 2x iStent MD 1.9 lower (2.91 lower to 0.89 lower) 148 (1 RCT) ⨁⨁◯◯ LOW a,b Follow-up: 12 months One MIGS procedure versus another procedure (non-MIGS) iStent+phaco vs phaco alone MD 1.9 lower (3.32 lower to 0.48 lower) 48 (1 observational study) ⨁◯◯◯ VERY LOW b,c Follow-up: 12 months iStent inject+phaco vs phaco alone MD 0.7 lower (1.27 lower to 0.13 lower) 570 (2 RCTs) ⨁⨁⨁◯ MODERATE a Follow-up: 24 months Hydrus+phaco vs phaco alone MD 1.8 lower (2.73 lower to 0.87 lower) 331 (1 RCT) ⨁⨁⨁⨁ HIGH Follow-up: 24 months Trab360+phaco vs phaco alone MD 2.8 lower (5.49 lower to 0.11 lower) 18 (1 RCT) ⨁◯◯◯ VERY LOW b,d Follow-up: 24 months Gold MicroShunt vs Ahmed glaucoma valve MD 0.7 lower (2.71 lower to 1.31 higher) 12 (1 RCT) ⨁◯◯◯ VERY LOW b,e Follow-up: 5 years iTrack+phaco vs filtration surgery+phaco MD 1.7 lower (3.29 lower to 0.11 lower) 59 (1 RCT) ⨁◯◯◯ VERY LOW b,f Follow-up: 12 months *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference; phaco: phacoemulsification (cataract surgery) GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect Explanations a. Possible risk of performance bias in personnel b. Wide confidence interval and/or sub-optimal information size c. Serious bias due to confounding d. High risk of performance and detection bias. 11 Executive summary e. High risk of attrition bias; unclear risk of bias in most other domains. f. High risk of selection, performance and attrition bias; unclear risk of detection and reporting bias.
Health economic evaluation
The lifetime total cost per patient for glaucoma treatment ranged between NOK 30 000 and NOK 84 000 depending on the treatment strategy and patient’s baseline disease stage. The incremental quality adjusted life years (QALYs) for MIGS between comparators ranged between – 0.080 and 0.057.
MIGS surgery is done at many public hospitals in Norway in addition to a few private clinics. There is a lack of formalised indications for the use of MIGS in Norway. MIGS is suitable for outpatient surgery without hospital admission. Ophthalmologists need specific MIGS training to perform the surgery (certification). The MIGS-procedures have a shorter learning curve than traditional glaucoma surgery, and has in other countries also been implemented by non-glaucoma specialists / general cataract surgeons for this reason (i.e. some benefit in terms of regional accessibility in Norway can be expected). MIGS procedures require less follow-up than traditional surgery, so there may be fewer post-intervention controls per patient in the hospital. Finally, a better treatment option may also lead to more patients being operated. The need for glaucoma surgery may increase due to increased population growth in the relevant age group. Experts predict that the demand for MIGS procedures will increase annually from today to twice as many by 2024.
There are potential benefits of MIGS. The central ethical concerns of MIGS implementation are, in terms of justice, to guarantee patients equal access to treatment, regardless of ability to pay, place of residence, social status, or cultural background. The challenges for patient autonomy seem manageable, if patients can be thoroughly informed about risks of and alternatives to a given MIGS procedure.
The strengths of CADTH’s and our health technology assessments include updated systematic searches in electronic databases, pre-specified inclusion and exclusion criteria, double independent screening of identified records, independent assessments of risk of bias in included studies, systematic data extraction and reporting, and assessments of the certainty of the evidence. We believe we have identified most eligiblie studies that were not included in CADTH’s HTA, thus providing a useful supplement. We had to make several assumptions to develop the six health economic models, leading to some uncertainty surrounding our economic results. MIGS is a heterogeneous group of devices with potentially different costs, risk profiles and relative treatment effects. We replicated the model from CADTH with respect to model structure and efficacy data. The input is adjusted according to Norwegian conditions. 12 Executive summary It is important to ask whether the introduction of MIGS will lead to a change in Norwegian practice. According to our clinical experts, the impact on practice will be limited. Our health economic evaluation is consistent with other evaluations on health economics, among others the CADTH report, regarding uncertainty around estimates due to lack of data. Cost components may be different in different countries. To obtain high quality documentation for the myriad of possible MIGS comparisons, there is a need for more well-designed randomised trials, with larger numbers of participants and longer follow-up. Further, detailed micro-costing of MIGS procedures may allow for greater certainty in the true absolute and incremental costs of MIGS to better inform the potential economic value of MIGS. For patients and clinicians, it would be helpful if evidence-based guidelines were developed or applied to a Norwegian setting in addition to local and/or national registrers. Studies on the most used MIGS procedures in Norway (as iStent, Xen, Preserflo) are included, but might not be well documented in this report, as some relevant clinical comparisons have not been conducted yet (to our knowledge). The evaluation of effect and cost-effectiveness might therefore have some limits.
MIGS with Hydrus Microstents combined with cataract surgery reduces intraocular pressure (IOP) at 24 months, compared to cataract surgery alone. MIGS with Hydrus Microstents probably reduces IOP at 12 months, compared to MIGS with 2x iStents. For other comparisons and outcomes, it is uncertain whether there is a difference in IOP reduction. Neither MIGS procedures nor alternative surgical strategies appear to be at high risk of adverse events, and it is uncertain whether complications occur more or less frequently in either category. Definitive conclusions on the cost-effectiveness of MIGS are uncertain, given the uncertainty in the analysis. The economic evaluation provided some scenarios where MIGS might be cost-effective, depending on comparator and disease stage. The clinical evidence on MIGS is limited. The main reason for this is the lack of comparative studies. Our health economic evaluation shows some scenarios where MIGS may be cost-effective, depending on comparator and disease stage. Our analysis puts individuals with glaucoma in severity class 1.