Highlights
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TVT IRIS Registry 1-year composite outcome results differ from those of the TVT RCT.
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TVT IRIS Registry tube and trabeculectomy failure rates are not significantly different.
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Trabeculectomy failure rates are not significantly different between the 2 TVT cohorts.
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Tube failure rates are significantly higher in the TVT IRIS Registry than in the TVT RCT.
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Reasons for failure rates may be non-Baerveldt tubes, greater severity, or differences in clinical practice.
Purpose
This study compared 1-year results for the composite treatment outcome from the Tube Versus Trabeculectomy (TVT) randomized controlled trial (RCT) to those from an IRIS Ⓡ (Intelligent Research In Sight) Registry cohort of analogous eyes.
Design
Retrospective clinical study with comparison to an RCT.
Methods
Subjects’ eyes in the IRIS Registry received either a glaucoma drainage implant (tube) or underwent trabeculectomy after a previous trabeculectomy and/or cataract extraction and had data for 1-year follow-up analyses.
Outcome
Eyes were classified as failing if they had hypotony (intraocular pressure (IOP) ≤5 mm Hg) or inadequate IOP control (IOP >21 mm Hg or not reduced at least 20% below baseline) on 2 consecutive follow-up visits after 3 months, a reoperation for glaucoma, or no light perception vision and as successful otherwise. Failure risk was compared by treatment, demographic, and clinical variables and was compared to analogous failure risks from the TVT RCT.
Results
The TVT IRIS Registry cohort included 419 eyes, 236 tube eyes (56.3%) and 183 trabeculectomy eyes (43.7%). In this cohort, there was no significant failure risk difference (12.3% for tube eyes and 16.4% for trabeculectomy eyes, P = 0.231). Comparing the studies, there was a significantly greater risk of failure in the TVT IRIS Registry tube eyes than in the TVT RCT tube eyes (3.8%; P <.001). Reasons for treatment failure included reoperations for glaucoma (none in the TVT RCT at 1 year).
Conclusions
Our results were different from those in the TVT RCT. Possible reasons include non-Baerveldt tubes, greater severity among tube eyes, and practice patterns that reflect real-world data, which are different than those in RCTs.
T The 1-year post-surgical treatment outcomes for the Tube Versus Trabeculectomy (TVT) randomized controlled trial (RCT), published in 2007, indicated a significantly greater risk of failure among eyes that received a trabeculectomy. The TVT RCT compared the safety and efficacy of a tube implantation, Baerveldt 350 glaucoma implant (BGI) (Johnson & Johnson Vision, Milpitas, California, USA) to trabeculectomy with mitomycin C “in eyes that had undergone previous filtering surgery, cataract surgery with intraocular lens implantation, or both.” These results still represent the highest level of evidence available for treatment of glaucoma uncontrolled with maximum tolerated medical therapy in such eyes, when incisional glaucoma surgery is needed. Since publication of the TVT RCT results, there has been a shift in clinical practice toward a greater use of tubes and a reduced use of trabeculectomies when incisional glaucoma surgery is performed. There also has been a reduction in the number of glaucoma surgeries performed, , attributed to improved glaucoma medication options. A shift in clinical practice inevitably changes the clinical characteristics of the patients (or in this case, the eyes) who receive each treatment option, such as having a tube implantation or a trabeculectomy.
Several retrospective studies evaluated outcomes for either trabeculectomies or tubes, including procedures in eyes with previous incisional glaucoma surgery, and found widely different 1-year failure rates for BGIs, Ahmed glaucoma valves (AGVs), and/or trabeculectomies. , , Two RCTs comparing AGV and BGI tubes, the Ahmed Baerveldt Comparison (ABC) study and the Ahmed Versus Baerveldt (AVB) study, found lower 1-year failure rates with BGI tubes, , but only the AVB study showed a statistically significant difference.
This research was supported by a 2018 Research to Prevent Blindness/American Academy of Ophthalmology Award for IRIS Ⓡ (Intelligent Research in Sight) registry research grant to compare 1-year post-surgical results from the TVT RCT cohort with results from an IRIS Registry cohort. Although many investigators have questioned the feasibility of replicating an RCT with real-world data (RWD), , exploring clinical questions with RWD will increase as the availability, size, and quality of such datasets improve. The present study compared 1-year composite treatment outcomes after tube versus trabeculectomy surgery from the TVT RCT to data from a cohort of analogous eyes from the IRIS Registry database. No previous direct comparisons of RCT and big-RWD results were found. In addition, the 1-year treatment outcomes for tube eyes were compared to outcomes for trabeculectomy eyes in the TVT IRIS Registry cohort.
METHODS
Design
The primary purposes of this study were to assess the feasibility of replicating an RCT using electronic health record data and to compare treatment outcomes using large, retrospective RWD. Because IRIS Registry data are deidentified, no informed consent was required, and the University of Miami Institutional Review Board approved this study as exempt. This research conformed to all country, federal, or state laws and adhered to tenets of the Declaration of Helsinki and Health Insurance Portability and Accountability Act. The TVT RCT is registered at www.clinicaltrials.gov (NCT00306852).
Patient Population, Data, and Eligibility Criteria
Study data were described in detail in the authors’ previous cohort selection and follow-up publication and are summarized here. IRIS Registry data were used to create a 1-year follow-up analysis cohort of 419 tube eyes (n = 236; 56.3%) and 183 trabeculectomy eyes (43.7%). Inclusion was based, as closely as possible, on the eligibility criteria of the TVT RCT (Supplemental Table 1). Supplemental Tables 2, 3, and 4 display baseline demographic and clinical characteristics by treatment groups of this TVT IRIS Registry 1-year follow-up cohort. Supplemental Table 1 contains the TVT RCT follow-up examination schedule and visit windows. The 1-week, 1-, 3-, and 6-month, and 1-year follow-up visits were designated using IRIS Registry data from the visit (within the window) closest to the TVT RCT scheduled follow-up time.
Outcomes
This TVT IRIS Registry research analyzed outcomes analogous to those of the TVT RCT (Supplemental Table 1). The primary composite treatment outcome was defined as 1) inadequate intraocular pressure (IOP) control (IOP >21 mm Hg or reduction <20% below baseline on 2 consecutive follow-up visits after 3 months); 2) hypotony (IOP ≤5 mm Hg on 2 consecutive follow-up visits after 3 months); 3) reoperation for glaucoma; or 4) no light perception (NLP) vision. Two secondary composite outcomes were defined by modifying only the inadequate IOP control criterion using lower IOP cutoff values (>17 mm Hg and >14 mm Hg, respectively). Inadequate IOP control and hypotony failures must have occurred at both the 6-month and 1-year follow-up visits. If that occurred, the failure date was considered to be the 6-month visit date. For failures based on a reoperation for glaucoma or NLP vision, the failure date was the date of the reoperation or date of first recorded NLP vision. , Reoperation for glaucoma included a cyclodestructive procedure or additional glaucoma surgery that required returning to the operating room. Lack of specificity for some Current Procedural Terminology (CPT) codes (American Medical Association, Washington, DC, USA; https://www.ama-assn.org/practice-management/cpt ) (66250 (repair or revision procedures on the anterior sclera of the eye); 66184 (revision of aqueous shunt to extraocular equatorial plate reservoir; without graft); and 66185 (revision with graft)) made it impossible to distinguish whether some eyes had a TVT RCT-defined reoperation or intervention. It was decided to classify these procedures as interventions. An eye that had not failed was classified as either a complete success (not on supplemental medical therapy) or a qualified success (on supplemental medical therapy) at the one-year follow-up visit.
Statistical Analysis
All eyes that had a 1-year follow-up visit and/or failed during the first year were included in these analyses. All results presented below are 1-year results, except as noted. The TVT IRIS Registry treatment groups were compared using independent sample t -tests for continuous variables and χ 2 , Fisher exact, or exact χ 2 tests for categorical variables. Risk factors for the composite treatment outcomes of success or failure were assessed using Kaplan-Meier survival analysis and univariate, bivariate, and forward stepwise multivariate Cox proportional hazards regression. Inter-study comparisons of percentages used χ 2 tests for a specified proportion and for failure reasons used exact χ 2 tests. These statistical analyses were performed using SAS version 9.4 software (SAS, Cary, North Carolina, USA). Inter-study comparisons of cumulative probabilities of failure (CPFs) were performed with 1-sample z -tests using Excel version 1902 software (Microsoft, Redmond, Washington, USA). A P value <.050 was considered statistically significant.
RESULTS
Primary Composite Outcome Success and Failure
Table 1 presents the composite treatment outcomes of the TVT IRIS Registry cohort by treatment, unadjusted for follow-up time (except as noted). There was a higher percentage of failing trabeculectomy eyes (16.4%) than tube eyes (12.3%), but this difference was not statistically significant ( P = .231). Trabeculectomy eyes had a significantly higher percentage of complete successes (52.9%) rather than qualified successes compared to tube eyes (34.3%) ( P < .001). When the TVT IRIS Registry cohort was compared to the TVT RCT cohort, there were significant differences in the percentage of tube eyes that failed (TVT IRIS Registry: 12.3%; TVT RCT: 3.8%; P <.001) but not in the percentage of trabeculectomy eyes that failed (TVT IRIS Registry: 16.4%; TVT RCT: 13.0%; P = .172) ( Table 2 ). There was also a significant difference in the percentage of successful trabeculectomy eyes that were a complete success (TVT IRIS Registry = 52.9%; TVT RCT = 63.0%; P = .010) but not in the percentage of successful tube eyes that that were a complete success (TVT IRIS Registry = 34.3%; TVT RCT = 33.7%; P = .928), see Table 2 .
| n (%) | |||||
|---|---|---|---|---|---|
| All Eyes | Tube Group | Trab Group | P Value | ||
| Outcomes for All Eyes in Analyses | n = 419 | n = 236 (56.3) | n = 183 (43.7) | χ Test | |
| Primary Composite Treatment Outcome | % Failure | 59 (14.1) | 29 (12.3) | 30 (16.4) | .231 |
| % Success | 360 (85.9) | 207 (87.7) | 153 (83.6) | ||
| Failure reason for unsuccessful eyes | n = 59 | 29 (49.2) | 30 (50.8) | ||
| Inadequate IOP control >21 mm Hg a | 3 (5.1) | 3 (10.3) | 0 (0.0) | .232 c | |
| Inadequate IOP control not 20% below baseline a | 21 (35.6) | 9 (31.0) | 12 (40.0) | ||
| Loss of light perception visual acuity | 2 (3.4) | 2 (6.9) | 0 (0.0) | ||
| Reoperation for glaucoma | 29 (49.2) | 13 (44.8) | 16 (53.3) | ||
| Persistent hypotony a | 4 (6.8) | 2 (6.9) | 2 (6.7) | ||
| Type of reoperation for glaucoma | CPT code | n = 29 | 13 (44.8) | 16 (55.2) | |
| Eyes that that that failed due to a | 66170 | 2 (6.9) | 1 (7.7) | 1 (6.3) | .272 c |
| reoperation for glaucoma | 66172 | 1 (3.5) | 0 (0.0) | 1 (6.3) | |
| 66179 | 2 (6.9) | 0 (0.0) | 2 (12.5) | ||
| 66180 | 12 (41.4) | 4 (30.8) | 8 (50.0) | ||
| 66710 | 12 (41.4) | 8 (61.5) | 4 (25.0) | ||
| Type of Reoperation for Glaucoma | CPT Code | n = 31 | 15 (48.4) | 16 (51.6) | |
| All eyes that had a | 66170 | 2 (6.5) | 1 (6.7) | 1 (6.3) | .263 c |
| reoperation for glaucoma | 66172 | 1 (3.2) | 0 (0.0) | 1 (6.3) | |
| 66179 | 2 (6.5) | 0 (0.0) | 2 (12.5) | ||
| 66180 | 13 (41.9) | 5 (33.3) | 8 (50.0) | ||
| 66710 | 13 (41.9) | 9 (60.0) | 4 (25.0) | ||
| Successful Eyes | n = 360 | 207 (57.5) | 153 (42.5) | ||
| Definition of Treatment Success | Qualified success | 208 (57.8) | 136 (65.7) | 72 (47.1) | <0.001 *** |
| Complete success | 152 (42.2) | 71 (34.3) | 81 (52.9) | ||
| Cumulative probabilities of failure: primary and secondary composite treatment outcomes b | |||||
| Definition of inadequate IOP control a | n = 419 | n = 236 | n = 183 | K-M test | |
| IOP >21 mm Hg or not reduced 20% below baseline | 16.4 | 19.3 | .346 | ||
| IOP >17 mm Hg or not reduced 20% below baseline | 23.1 | 21.5 | .747 | ||
| IOP >14 mm Hg or not reduced 20% below baseline | 38.5 | 35.8 | .753 | ||
a Inadequate IOP control or hypotony criteria must have been present on 2 consecutive follow-up visits after 3 months for the eye to quality as a failure for inadequate IOP control or hypotony, respectively.
b Eyes with persistent hypotony (IOP <=5 mm Hg on two consecutive follow-up visits after three months), loss of light perception vision, or reoperation for glaucoma were classified as failures in all three analyses. These three analyses for the Cumulative Probabilities of Failure were adjusted for follow-up time.
| Outcome | TVT IRIS Registry Cohort n (%) | TVT RCT Alternate Study Cohort n (%) | P Value | ||
|---|---|---|---|---|---|
| Inter-study comparisons with the complete 1-year follow-up analysis cohorts: primary composite outcome a | |||||
| % Failed | Tube | 29 (12.3) | TVT RCT: Tube | 4 (3.8) | <.001*** |
| % Failed | Trab | 30 (16.4) | TVT RCT: Trab | 13 (13.0) | .172 |
| Inter-study comparisons with only the eyes that were successful a | |||||
| % Complete success | Tube | 71 (34.3) | TVT RCT: Tube | 35 (33.7) | .982 |
| % Complete success | Trab | 81 (52.9) | TVT RCT: Trab | 63 (63.0) | .010** |
| Inter-study comparisons in eyes that Failed b | |||||
| Failure reason | n = 59 | n = 17 | |||
| Inadequate IOP control c | Both | 24 (40.7) | TVT RCT: Both | 14 (82.4) | .001** |
| Loss of light perception | Both | 2 (3.4) | TVT RCT: Both | 0 (0.0) | |
| Reoperation for glaucoma | Both | 29 (49.2) | TVT RCT: Both | 0 (0.0) | |
| Persistent hypotony d | Both | 4 (6.8) | TVT RCT: Both | 3 (17.7) | |
| Failure reason | n = 29 | n = 4 | |||
| Inadequate IOP control c | Tube | 12 (41.4) | TVT RCT: Tube | 4 (100) | .207 |
| Loss of light perception | Tube | 2 (6.9) | TVT RCT: Tube | 0 (0.0) | |
| Reoperation for glaucoma | Tube | 13 (44.8) | TVT RCT: Tube | 0 (0.0) | |
| Persistent hypotony d | Tube | 2 (6.9) | TVT RCT: Tube | 0 (0.0) | |
| Failure reason | n = 30 | n = 13 | |||
| Inadequate IOP control c | Trab | 12 (40.0) | TVT RCT: Trab | 10 (76.9) | .003** |
| Loss of light perception | Trab | 0 (0.0) | TVT RCT: Trab | 0 (0.0) | |
| Reoperation for glaucoma | Trab | 16 (53.3) | TVT RCT: Trab | 0 (0.0) | |
| Persistent hypotony d | Trab | 2 (6.7) | TVT RCT: Trab | 3 (23.1) | |
a χ 2 tests for a specified proportion.
c IOP >21 mm Hg or not reduced at least 20% below baseline on 2 consecutive follow-up visits after 3 months.
d IOP ≤ 5 mm Hg on 2 consecutive follow-up visits after 3 months.
For the TVT IRIS Registry cohort, the reasons for treatment failures are listed in Table 1 . The most common reason in both treatment groups was a reoperation for glaucoma (tube eyes n = 13 [44.8%]; trabeculectomy eyes n = 16 [53.3%]). There were 12 eyes in each group that failed with inadequately controlled IOP. Two of these eyes (both tube eyes) later required reoperation for glaucoma. There was no significant difference between treatment groups in the (1) distribution of reasons for failure ( P = .232) and type of reoperation for (2) eyes that failed because of a reoperation for glaucoma ( P = .272) and (3) all eyes that had a reoperation for glaucoma ( P = .263). The majority of reoperations for tube eyes were cyclophotocoagulation, while the majority for trabeculectomy eyes were tube shunt implantations (see Table 1 ).
Comparing the 2 TVT cohorts, for eyes that failed, there was a significant difference in the reasons for treatment failure ( P = .001, Table 2 ). In the TVT IRIS Registry, 29 eyes (49.2%) failed due to a reoperation for glaucoma, whereas in the TVT RCT, none failed for this reason. In the TVT RCT, the most common reason for failure was inadequate IOP control (n = 14; 82.4%). For the tube eyes, there was no significant difference between the 2 TVT cohorts in the reasons for treatment failure ( P = .207). This was possibly due to low power, because the TVT RCT had only 4 failing tube eyes. For the trabeculectomy eyes, there was a significant difference between the 2 TVT cohorts in the reasons for treatment failure ( P = .003, Table 2 ).
Primary and Secondary Composite Treatment Outcome Survival
The Figure displays the survival curves and Table 1 presents the CPFs for the treatment groups’ composite outcomes for each IOP cutoff value. For the primary composite treatment outcome (IOP cutoff >21 mm Hg), the CPF was 16.4% for tube eyes and 19.3% for trabeculectomy eyes ( P = .346) ( Figure 1 , A). When the IOP cutoff was >17 mm Hg, the CPF was 23.1% for tube eyes and 21.5% for trabeculectomy eyes ( P = .747) ( Figure 1 , B). When the IOP cutoff was >14 mm Hg, the CPF was 38.5% for tube eyes and 35.8% for trabeculectomy eyes ( P = .753) ( Figure 1 , C). Therefore, no significant differences were observed among treatment groups using this broad range of IOP cutoffs (>21 mm Hg, >17 mm Hg, and >14 mm Hg, respectively) to determine failure. In the TVT RCT, the CPFs were greater for the trabeculectomy eyes for all 3 IOP cutoffs. In a comparison between the TVT RCT cohort to the TVT IRIS Registry cohort, there were significant differences between the CPFs in the 2 studies for tube eyes at all IOP cutoffs (all P < .001), but for trabeculectomy eyes, the difference was significant only for an IOP cutoff of >14 mm Hg ( P = .027) (see Table 3 ).
| Compare the 2 TVT cohorts’ CPFs at one year | ||||||||
|---|---|---|---|---|---|---|---|---|
| Variables | Values | Number of Eyes in TVT IRIS Registry Cohort | TVT IRIS Registry CPF | 95% CI of TVT IRIS Registry CPF | TVT RCT CPF | Difference in Studies’ CPFs | P Value (difference in studies’ CPFs) | |
| Treatment group | Tube | 236 | 16.4 | (10.5–22.4) | 3.9 | 12.5 | <.001 | *** |
| IOP >21 cutoff | Trab | 183 | 19.3 | (13.0–25.5) | 13.5 | 5.8 | .071 | |
| Treatment group | Tube | 236 | 23.1 | (17.1–29.1) | 4.9 | 18.2 | <.001 | *** |
| IOP >17 cutoff | Trab | 183 | 21.5 | (15.0–27.9) | 16.7 | 4.8 | .147 | |
| Treatment group | Tube | 236 | 38.5 | (31.5–45.4) | 11.9 | 26.6 | <.001 | *** |
| IOP >14 cutoff | Trab | 183 | 35.8 | (28.3–43.3) | 27.4 | 8.4 | .027 | * |
| Stratum | Prev cat extraction | 288 | 19.2 | (13.6–24.7) | 11.6 | 7.6 | .007 | ** |
| Prev trab or comb proc a | 131 | 14.5 | (7.9–21.2) | 6.3 | 8.3 | .015 | * | |
| Age group | <60 years | 54 | 13.5 | (3.3–23.6) | 14.4 | -0.9 | .858 | |
| ≥60–<70 years | 105 | 19.6 | (9.4–29.9) | 12.1 | 7.5 | .149 | ||
| ≥70–<80 years | 184 | 19.2 | (12.8–25.5) | 6.9 | 12.3 | .000 | *** | |
| ≥80 years | 76 | 14.3 | (5.6–23.0) | 2.4 | 11.9 | .007 | ** | |
| Gender | Males | 197 | 21.7 | (14.4–29.0) | 9 | 12.7 | .001 | *** |
| Females | 222 | 14.3 | (9.1–19.4) | 8.3 | 6 | .023 | * | |
| Race/ Ethnicity | White | 219 | 13.6 | (8.6–18.5) | 7.8 | 5.8 | .024 | * |
| Black | 122 | 15.9 | (8.4–23.3) | 11.8 | 4.1 | .285 | ||
| Hispanic | 40 | 25 | (10.8–39.3) | 3.7 | 21.3 | .003 | ** | |
| Asian b | 9 | 70.8 | (26.0–115.7) | 0 | 70.8 | .002 | ** | |
| Other/Mixed b | 29 | 23 | (6.8–39.1) | 0 | 23 | .005 | ** | |
| Diabetes mellitus | NO | 265 | 18.3 | (13.2–23.5) | 9.8 | 8.5 | .001 | ** |
| YES | 154 | 16.4 | (8.7–24.1) | 8.1 | 8.3 | .034 | * | |
| Hypertension | NO | 128 | 19.4 | (11.7–27.1) | 7.9 | 11.5 | .004 | ** |
| YES | 291 | 17 | (11.7–22.3) | 9.6 | 7.4 | .006 | ** | |
| Lens status | Phakic | 98 | 17.3 | (8.6–25.9) | 9.5 | 7.8 | .080 | |
| Pseudophakic c | 321 | 17.8 | (12.8–22.7) | 8.4 | 9.4 | .000 | *** | |
| Previous Intraocular Surgeries (PIS): total number groups | 1 PIS | 214 | 16.3 | (10.7–21.8) | 8.7 | 7.6 | .008 | ** |
| 2 PIS | 139 | 18.9 | (11.7–26.1) | 7.5 | 11.4 | .002 | ** | |
| 3+ PIS | 66 | 21.1 | (5.4–36.9) | 12.5 | 8.6 | .283 | ||
| Last PIS: total months before baseline | ≤6 months | 120 | 16.9 | (9.6–24.3) | 13.3 | 3.6 | .337 | |
| >6 months | 299 | 18 | (12.7–23.4) | 8.5 | 9.5 | .000 | *** | |
| Glaucoma type | Primary | 383 | 17.8 | (13.2–22.4) | 7.4 | 10.4 | <.001 | *** |
| Secondary | 36 | 16.8 | (3.3–30.2) | 18.2 | -1.4 | .836 | ||
| Baseline number of medications group | 0–1 glaucoma meds | 35 | 13.3 | (1.1–25.6) | 9.5 | 3.8 | .538 | |
| 2–3 glaucoma meds | 133 | 12.9 | (6.5–19.3) | 8.2 | 4.7 | .151 | ||
| 4–6 glaucoma meds | 251 | 20.9 | (14.7–27.1) | 8.8 | 12.1 | .000 | *** | |
| Baseline Intraocular Pressure group | <23 mm Hg | 163 | 28.3 | (19.7–36.9) | 12.2 | 16.1 | .000 | *** |
| 23–26 mm Hg | 84 | 13.1 | (5.0–21.1) | 4.8 | 8.3 | .044 | * | |
| >26 mm Hg | 172 | 10.1 | (5.0–15.1) | 8.1 | 2 | .447 | ||
| Baseline visual acuity group | ≥20/30 | 80 | 16.1 | (6.8–25.4) | 8.8 | 7.3 | .123 | |
| <20/30 – >20/200 | 281 | 17.7 | (12.3–23.1) | 9 | 8.7 | .002 | ** | |
| ≤20/200 | 58 | 20.2 | (8.9–31.4) | 6.9 | 13.3 | .021 | * | |
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