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Dr Prata raises several points regarding the iStent inject pivotal trial (Reference 1 in their correspondence). It is worth noting that all aspects of the trial’s study design were completed in close communication with the US Food and Drug Administration and according to Food and Drug Administration Minimally Invasive Glaucoma Surgical (MIGS) Guidance and American National Standards Institute Guidance.1Food and Drug Administration Center for Devices and Radiological HealthPremarket studies of implantable minimally invasive glaucoma surgical (MIGS) devices: guidance for industry and Food and Drug Administration staff.www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM433165.pdfDate accessed: August 28, 2019Google Scholar,2American National Standards Institute (ANSI) for Ophthalmics. Z80.27-2014: Implantable glaucoma devices. The Vision Council, Alexandria, VA2014Google Scholar The authors cite the possibility of regression to the mean. This is a statistical phenomenon that can be most effectively alleviated by conducting a well-designed, prospective, randomized controlled trial (RCT) with an appropriate control arm,3Barnett A.G. van der Pols J.C. Dobson A.J. Regression to the mean: what it is and how to deal with it.Int J Epidemiol. 2005; 34: 215-220Crossref PubMed Scopus (1147) Google Scholar which is precisely the design of the present study. The baseline attributes of the 2 study groups were similar, further minimizing the possibility of bias. Robust guidelines (i.e., Food and Drug Administration, American National Standards Institute) do not necessitate multiday baseline intraocular pressure (IOP) measurements. The standard in glaucoma device trials is the baseline assessment of post-washout mean diurnal IOP (DIOP), consisting of the average of 3 measurements taken over 1 day using the widely accepted 2-person method. This rigorous metric requires considerable expense, patients’ full-day commitment, and risks of washing out patients who require treatment. Moreover, the study required screening IOP measurement in addition to baseline measurements. Thus, subject selection indeed incorporated multiple individual IOP measures. These inclusion criteria were carefully designed to ensure that all enrolled patients had primary open-angle glaucoma (POAG) and needed additional treatment. The high screen failure rate of approximately 42% in the present study underscores the challenge of enrolling the necessary 505 subjects for the trial. The magnitude of IOP reduction after phacoemulsification was another topic raised. In the setting of different study designs and baseline parameters (e.g., medicated vs unmedicated IOP, different baseline IOPs, different glaucoma types), disparate studies cannot be directly compared. The correspondence cites prior work showing a 1.5–2.0 mmHg decrease in IOP after phacoemulsification alone in eyes with POAG. However, the referenced manuscript cited studies of medicated POAG, which included normal-tension glaucoma; the mean preoperative IOP in these studies was 17.7 mmHg on 1.7 mean medications. In contrast, the control group in the present study had a baseline post-washout DIOP of 24.5 mmHg on 0 medications and excluded normal-tension glaucoma. It is widely known that higher preoperative IOP produces greater postphacoemulsification IOP decreases. Thus, the present study’s preoperative DIOP would be expected to result in greater IOP reduction than that of studies with lower baseline pressures. Consistent with this expectation, the observed IOP reduction in the study’s control group was greater than that in the aforementioned article and notably was similar to the control groups of other large MIGS RCTs. The correspondence cites “artificially high magnitude of IOP reduction” with iStent inject. Given that both study groups followed the same IOP inclusion criteria and had similar baseline DIOP, this rationale would apply to both groups equally. In studies outside the confines of RCTs, the IOP reduction of iStent inject has been even more marked.4Clement C.I. Howes F. Ioannidis A.S. et al.One-year outcomes following implantation of second-generation trabecular micro-bypass stents in conjunction with cataract surgery for various types of glaucoma or ocular hypertension: multicenter, multi-surgeon study.Clin Ophthalmol. 2019; 13: 491-499Crossref PubMed Scopus (29) Google Scholar,5Hengerer F.H. Auffarth G.U. Riffel C. et al.Prospective, non-randomized, 36-month study of second-generation trabecular micro-bypass stents with phacoemulsification in various types of glaucoma.Ophthalmol Ther. 2018; 7: 405-415Crossref PubMed Scopus (41) Google Scholar MIGS RCTs produce clinical situations rarely encountered outside controlled trials, specifically washed-out IOP both preoperatively and postoperatively. Comparing results of stringently controlled trials with less controlled studies with different requirements for preoperative IOP and medication washout is simply without merit. The correspondence suggests that study outcomes may be statistically but not clinically significant. Landmark glaucoma trials have established the clinical importance of any degree of IOP lowering in glaucoma treatment. For example, every 1 mmHg IOP reduction produced a 10% or 19% lower risk of glaucoma progression (Early Manifest Glaucoma Trial, Canadian Glaucoma Study) and a 10% lower risk of glaucoma development (Ocular Hypertension Treatment Study). Meanwhile, decreasing medication burden in any capacity has substantial value given the well-known downsides of medications, such as poor adherence, ocular surface damage, side effects, and costs. Thus, the fact that 84% of iStent inject eyes were medication free at 2 years is particularly noteworthy. It is also important to keep in mind that large RCTs report IOP and medication outcomes as mean values; however, this does not capture individual patient-level benefits of lowering IOP or using fewer drops. The iStent inject pivotal study provides one of the few robust, randomized, controlled datasets in MIGS. The study gives valuable data on a device (iStent inject) that is becoming increasingly offered as an attractive treatment option for glaucoma patients. We appreciate the authors’ interest in our article as well as the opportunity to address their concerns. Re: Samuelson et al.: Prospective, randomized, controlled pivotal trial of an ab interno implanted trabecular micro-bypass in primary open-angle glaucoma and cataract: two-year results (Ophthalmology. 2019;126:811-821)OphthalmologyVol. 127Issue 2PreviewWe would like to congratulate Samuelson et al1 for the well-written article evaluating the safety and effectiveness of an ab interno implanted trabecular micro-bypass device (iStent inject; Glaukos Corporation, San Clemente, CA) in combination with cataract surgery in subjects with mild-to-moderate primary open-angle glaucoma (POAG). Many patients submitted to cataract surgery have glaucoma as a comorbid condition. Unless intraocular pressure (IOP) is uncontrolled despite maximum tolerated medication, a conventional combined glaucoma-cataract procedure (phacotrabeculectomy) is infrequently performed in eyes with mild-to-moderate disease owing to its unsatisfying safety profile and postoperative complications. Full-Text PDF