Results from the Primary Tube Versus Trabeculectomy (PTVT) Study and Translation to Clinical Practice

Abstract

Purpose of review:

The Primary Tube Versus Trabeculectomy (PTVT) Study is a multicenter randomized clinical trial comparing the safety and efficacy of tube shunt surgery and trabeculectomy with mitomycin C (MMC) in eyes without previous incisional ocular surgery. This article reviews results from the PTVT Study and suggests how they may be translated to clinical practice.

Recent findings:

Tube shunt surgery had a higher failure rate than trabeculectomy with MMC in the PTVT Study, and the difference was statistically significant at 1 year but not at 3 years and 5 years. Both surgical procedures reduced intraocular pressure (IOP) to the low teens throughout 5 years of follow-up. Mean IOPs were lower after trabeculectomy with MMC compared with tube shunt implantation, and the differences were statistically significant during the first postoperative year and at 3 years. The greater IOP reduction after trabeculectomy with MMC was achieved with significantly fewer glaucoma medications relative to tube shunt placement. Surgical complications were common in the PTVT Study, but most were transient and self-limited. The incidence of early postoperative complications was significantly higher after trabeculectomy with MMC than tube shunt surgery. The rates of late postoperative complications, cataract progression, and vision loss were similar with both surgical procedures. Serious complications producing vision loss and/or requiring a reoperation to manage the complication developed more frequently after trabeculectomy with MMC compared with tube shunt surgery, and the difference was statistically significant at 1 year but not at 3 years and 5 years postoperatively.

Summary:

Tube shunt implantation and trabeculectomy with MMC are both viable surgical options for managing glaucoma in patients without previous incisional ocular surgery. Results from the PTVT Study support further expansion of tube shunt use beyond refractory glaucomas.

INTRODUCTION

Glaucoma surgery is indicated when medical therapy and appropriate laser treatment do not achieve adequate intraocular pressure (IOP) reduction. The surgical options for managing glaucoma have increased exponentially in recent years with the introduction of minimally invasive glaucoma surgery (MIGS). However, trabeculectomy and tube shunt surgery remain the most effective procedures to lower IOP. A dose-response relationship exists between IOP control and glaucomatous progression [1]. Glaucoma procedures that produce greater IOP reduction are more likely to stabilize the disease.

Medicare claims data [2, 3■] and surveys of the American Glaucoma Society (AGS) membership [4–7] demonstrate that tube shunts are being used with increasing frequency as an alternative to trabeculectomy. No clear consensus exists among glaucoma surgeons regarding the preferred initial operation for medically uncontrolled glaucoma in eyes without prior ocular surgery [6,7]. An anonymous survey of AGS members in 2016 showed that trabeculectomy with mitomycin C (MMC) and tube shunt surgery were the most popular primary incisional glaucoma surgeries in 59% and 23% of patients, respectively [7].

The Primary Tube Versus Trabeculectomy (PTVT) Study is a multicenter randomized clinical trial comparing the safety and efficacy of tube shunt surgery and trabeculectomy with MMC as a primary incisional glaucoma procedure. Eyes without previous ocular surgery were enrolled and randomly assigned to treatment with a 350-mm² Baerveldt glaucoma implant (Johnson & Johnson Vision, Santa Ana, CA) or trabeculectomy with MMC. The goal of this investigator-initiated study is to provide information that will assist in surgical decision making in similar patient groups.

METHODOLOGY

The design and methods of the PTVT Study were previously described in detail [8]. The inclusion and exclusion criteria for the study are listed in Table 1. Only 1 eye of eligible patients was included in the study. Enrolled patients were randomly assigned to treatment with a tube shunt or trabeculectomy with MMC. Patients in the tube group had placement of a 350-mm² Baerveldt glaucoma implant in the superotemporal quadrant with complete flow restriction through the tube at the time of implantation. Patients in the trabeculectomy group underwent a superior trabeculectomy with a standard dosage of MMC of 0.4 mg/ml for 2 minutes. All investigators in the PTVT Study were glaucoma surgeons who had experience performing both surgical procedures under study. Follow-up visits were scheduled 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, 18 months, 2 years, 3 years, 4 years, and 5 years postoperatively.

Table 1.

Patient Eligibility Criteria for the PTVT Study

Inclusion criteria

Age 18 to 85 years Glaucoma inadequately controlled on tolerated medical therapy with IOP ≥ 18 mm Hg and ≤ 40 mm Hg No previous incisional ocular surgery

Exclusion criteria

No light perception vision Pregnant or nursing women Narrow anterior chamber angle Iris neovascularization or active proliferative retinopathy Iridocorneal endothelial syndrome Epithelial or fibrous downgrowth Chronic or recurrent uveitis Steroid-induced glaucoma Severe posterior blepharitis Unwilling to discontinue contact lens use after surgery Previous cyclodestructive procedure Conjunctival scarring from prior ocular trauma of cicatrizing disease precluding a trabeculectomy superiorly Functionally significant cataract Need for glaucoma surgery combined with other ocular procedures (i.e. cataract surgery, penetrating keratoplasty, or retinal surgery) or anticipated need for additional ocular surgery Unwilling or unable to give consent, unwilling to accept randomization, or unable to return for scheduled protocol visits

IOP = intraocular pressure

Failure was defined a priori as IOP > 21 mmHg or reduced < 20% below baseline on 2 consecutive follow-up visits after 3 months, IOP ≤ 5 mmHg on 2 consecutive visits after 3 months, reoperation for glaucoma, or loss of light perception vision. Reoperation for glaucoma or a complication was defined as surgical management that required a return to the operating room. Cyclodestruction was also considered a reoperation for glaucoma, regardless of whether it was performed in the clinic or operating room. Interventions performed at the slit lamp, such as needling procedures and laser suture lysis, were not counted as glaucoma reoperations. Eyes that had not failed by the above criteria and were not on supplemental medical therapy were categorized as complete successes, and those receiving glaucoma medications were classified as qualified successes. Investigators provided a reason for loss of 2 or more lines of Snellen VA from baseline at follow-up visits after 3 months. Early postoperative complications were defined as surgical complications occurring within 1 month following randomized surgical treatment, and late postoperative complications were complications developing after 1 month postoperatively. Serious complications were defined as surgical complications that produced vision loss of 2 or more Snellen lines and/or required a reoperation to manage the complication. Cataracts were considered to have progressed if there was loss of 2 or more Snellen lines attributed to cataract or if cataract surgery was performed. Study outcomes were regularly reviewed by an independent Safety and Data Monitoring Committee.

RESULTS

Results from the PTVT Study have been previously published through 5 years of follow-up [9,10,11■,12■■,13■■].

Baseline Characteristics of Study Population

A total of 242 eyes of 242 patients were enrolled at 16 Clinical Centers, including 125 patients in the tube group and 117 patients in the trabeculectomy group [9]. The age (mean ± SD) of the study population at enrollment was 61.4 ± 11.8 years, and 66% of patients were male. The baseline IOP (mean ± SD) of the overall study group was 23.6 ± 5.3 mmHg, and the number of glaucoma medications (mean ± SD) was 3.2 ± 1.1. The most common diagnosis was primary open-angle glaucoma in 218 eyes (90%). The mean deviation with Humphrey visual field testing (mean ± SD) was −14.6 ± 9.9 dB at baseline. No significant differences in any of the demographic or ocular characteristics were seen between treatment groups at enrollment suggesting that randomization was effective in creating two balanced treatment groups.

Operative Data and Postoperative Interventions

A fornix-based conjunctival flap was used in a majority of patients in the tube group (88%) and trabeculectomy group (84%) [9]. An intraluminal rip-cord suture was the most common method of tube occlusion (67%), and tube fenestration was frequently performed (47%) for IOP reduction in the early postoperative period. The most frequent postoperative interventions were rip-cord removal (52%) and laser suture lysis (29%) in the tube and trabeculectomy groups, respectively [13■■]. The rate of postoperative interventions was similar between the tube group (62%) and trabeculectomy group (60%) during 5 years of follow-up (p = 0.58).

Surgical Failure

Kaplan-Meier plots of the cumulative probability of failure are shown in Figure 1. The probability of failure was 17.3% in the tube group and 7.9% in the trabeculectomy group at 1 year, a difference that was statistically significant (p = 0.01) [9]. The failure rates increased to 33% at 3 years and 42% at 5 years in the tube group, and they rose to 28% at 3 years and 35% at 5 years in the trabeculectomy group [10,12■■]. The differences in failure rates between groups were no longer statistically significant at 3 years (p = 0.17) and 5 years (p = 0.21). Although the overall success rate was similar between the two treatment groups, the rate of complete success was significantly higher in the trabeculectomy group (34%) compared with the tube group (9%) at 5 years (p < 0.001) [12■■]. Inadequate IOP reduction (i.e., IOP > 21 mmHg or reduced < 20% below baseline on 2 consecutive follow-up visits after 3 months) was the most common cause for treatment failure during the first 5 years of follow-up in both the tube group (63% of failures) and trabeculectomy group (61% of failures). A significant difference in the distribution of reasons for failure was seen between treatment groups (p = 0.016) with more failures because of glaucoma reoperations in the tube group (37% of failures) than the trabeculectomy group (24% of failures), and more hypotony failures in the trabeculectomy group (10% of failures) relative to the tube group (0% of failures).

Figure 1.

Kaplan-Meier plots showing the cumulative probability of failure in the PTVT Study. Adapted from [12■■].

Baseline demographic and clinical characteristics were evaluated as possible predictors for failure, and only preoperative IOP was significantly associated with treatment outcome in univariable and multivariable analyses [11■,12■■]. A significant treatment interaction was observed between preoperative IOP and failure. Figure 2 shows Kaplan-Meier survival analysis subdividing patients based on treatment group and preoperative IOP. In the tube group, there was an inverse relation between preoperative IOP and failure. In the trabeculectomy group, the rate of failure was less influenced by preoperative IOP. As a result, the tube group had a higher failure rate than the trabeculectomy group at lower levels of preoperative IOP. However, this relationship was reversed at higher levels of preoperative IOP, wherein the tube group had a lower failure rate than the trabeculectomy group.

Figure 2.

Kaplan-Meier plots showing the cumulative probability of failure in the PTVT Study among patients with preoperative intraocular pressure < 21 mmHg (A), 21–25 mmHg (B), and > 25 mmHg (C). Adapted from [12■■].

Intraocular Pressure and Glaucoma Medical Therapy

Data on IOP and glaucoma medical therapy at baseline and at follow-up visits are presented in Table 2. Patients who underwent additional glaucoma surgery were censored from analysis after reoperation. Mean IOPs were lower in the trabeculectomy group relative to the tube group throughout 5 years of follow-up, except at 4 years when they were equivalent [9,10,12■■]. The IOP difference was statistically significant during the first postoperative year and at 3 years, but not at other timepoints. The lower pressures in the trabeculectomy group were achieved with significantly fewer glaucoma mediations compared with the tube group at all follow-up visits. At 5 years, a majority of patients in the tube group (69%) and trabeculectomy group (56%) had an IOP of 14 mmHg or less [12■■].

Table 2.

Intraocular Pressure and Medical Therapy in the PTVT Study

	Tube Group	Trabeculectomy Group	P-value*
Baseline
IOP (mm Hg)	23.3 ± 4.9	23.9 ± 5.7	0.35
Glaucoma medications	3.1 ± 1.1	3.2 ± 1.1	0.56
N	125	117
1 day
IOP (mm Hg)	19.0 ± 9.7	16.3 ± 9.2	0.029
N	125	116
1 week
IOP (mm Hg)	18.2 ± 8.5	15.1 ± 9.2	0.007
Glaucoma medications	1.1 ± 1.4	0.1 ± 0.5	< 0.001
N	120	116
1 month
IOP (mm Hg)	19.7 ± 7.3	13.1 ± 6.3	< 0.001
Glaucoma medications	1.4 ± 1.5	0.2 ± 0.8	< 0.001
N	124	115
3 months
IOP (mm Hg)	18.0 ± 5.9	12.5 ± 4.9	< 0.001
Glaucoma medications	1.9 ± 1.4	0.6 ± 1.2	< 0.001
N	121	113
6 months
IOP (mm Hg)	14.7 ± 4.4	12.8 ± 4.8	0.003
Glaucoma medications	2.1 ± 1.4	0.6 ± 1.2	< 0.001
N	112	109
1 year
IOP (mmHg)	13.8 ± 4.1	12.4 ± 4.4	0.012
Glaucoma medications	2.1 ± 1.4	0.9 ± 1.4	< 0.001
N	108	105
18 months
IOP (mmHg)	13.5 ± 4.1	12.8 ± 4.7	0.33
Glaucoma medications	2.1 ± 1.3	0.8 ± 1.3	< 0.001
N	99	97
2 years
IOP (mmHg)	13.6 ± 3.9	12.9 ± 5.2	0.28
Glaucoma medications	2.2 ± 1.0	1.0 ± 1.5	< 0.001
N	99	96
3 years
IOP (mmHg)	13.9 ± 4.2	12.1 ± 4.8	0.010
Glaucoma medications	2.1 ± 1.4	1.2 ± 1.5	< 0.001
N	87	88
4 years
IOP (mmHg)	13.5 ± 3.5	13.5 ± 5.4	0.98
Glaucoma medications	2.3 ± 1.4	1.3 ± 1.4	< 0.001
N	83	79
5 years
IOP (mmHg)	13.4 ± 3.5	13.0 ± 5.2	0.52
Glaucoma medications	2.2 ± 1.3	1.3 ± 1.4	< 0.001
N	74	75

IOP = intraocular pressure; N = number of patients

Data are presented as mean ± standard deviation

Data censored after a reoperation for glaucoma

^*Student t-test

Adapted from [9,12■■].

Visual Acuity

Reduction in VA occurred in both the tube and trabeculectomy group during 5 years of follow-up, but Snellen and ETDRS VA were similar between treatment groups at 5 years [12■■]. The rate of loss of 2 or more lines of Snellen VA from baseline was similar in the tube group (32%) and trabeculectomy group (31%) after 5 years (p = 1.00). Some of the causes of vision loss were not directly attributable to the surgical procedures under study, such as branch retinal vein occlusion and age-related macular degeneration. The proportion of patients who experienced loss of 2 or more Snellen lines was similar among patients who did develop postoperative complications (31%) and those who did not (32%) during 5 years of follow-up (p = 1.00) [13].

Postoperative Complications

A large number of complications were observed in the PTVT Study, but most were transient and self-limited [9,10,13■■]. The rate of early postoperative complications (i.e., surgical complications occurring within 1 month of surgery) was significantly higher in the trabeculectomy group (34%) than the tube group (19%) in the trial (p = 0.013) [13■■]. Late postoperative complications (i.e., surgical complications developing after 1 month postoperatively) were noted with similar frequency in the tube group (22%) and the trabeculectomy group (27%) after 5 years (p = 0.37). All complications are not equal in severity, and serious complications producing vision loss and/or requiring a reoperation occurred at a higher rate in the trabeculectomy group (7%) than the tube group (1%) at 1 year (p = 0.03) [9]. However, the differences in the rate of serious complications were no longer statistically significant at 3 years (p = 0.11) and 5 years (p = 0.11) [10,13■■]. Anterior chamber shallowing and choroidal effusion were common early postoperative complications in the tube and trabeculectomy groups, and bleb encapsulation was the most common late postoperative complication in both treatment groups [9,10,13■■].

Cataract Progression

All patients in the PTVT Study were phakic at the time of enrollment. Cataract progression was common but occurred with similar frequency in the tube group (52%) and the trabeculectomy group (44%) during 5 years of follow-up (p = 0.30) [13■■]. The cumulative rate of cataract extraction was not significantly different in the tube group (56%) and trabeculectomy group (42%) after 5 years (p = 0.21).

CONCLUSIONS

The PTVT Study enrolled patients with medically uncontrolled glaucoma without previous incisional ocular surgery and randomly assigned treatment to tube shunt implantation or trabeculectomy with MMC [8]. Mean IOPs were lower after trabeculectomy with MMC than tube shunt placement throughout 5 years of follow-up, and the differences were statistically significant during the first postoperative year and at 3 years [9,10,12■■]. The greater IOP reduction after trabeculectomy with MMC was achieved with significantly fewer glaucoma medications relative to tube shunt surgery. Surgical failure occurred at a higher rate following tube shunt implantation compared to trabeculectomy with MMC, and the difference was statistically significant at 1 year but not at 3 years and 5 years. A large number of surgical complications were observed in the PTVT Study, but most were transient and resolved spontaneously [9.10.13■■]. The incidence of early postoperative complications was significantly higher after trabeculectomy with MMC relative to tube shunt surgery. The rates of late postoperative complications, cataract progression, and vision loss were similar with both surgical procedures. Serious complications producing vision loss and/or requiring reoperation developed more commonly after trabeculectomy with MMC than tube shunt surgery, and the difference was statistically significance at 1 year but not at 3 years and 5 years postoperatively.

The PTVT Study has several limitations. The trial enrolled patients who met specific inclusion and exclusion criteria, and they underwent a standard trabeculectomy with MMC or 350-mm² Baerveldt implantation. Study results cannot be generalized to different patient groups or implant types. Although aspects of both surgical procedures were standardized, some variation in technique occurred because surgeons were allowed sufficient latitude to perform the operations in a manner in which they were comfortable. There were no standard definitions or quantification of surgical complications. The low incidence of certain complications and the small sample size of many patient subgroups limited the power of the study to detect significant differences. The patients and investigators were not masked to the randomized treatment assignment, and this is a potential source of bias.

TRANSLATION TO CLINICAL PRACTICE

Although randomized clinical trials offer the highest quality of evidence in medicine, it is frequently difficult to translate results into clinical practice [14–16]. A small percentage of patients receiving care may fully meet the eligibility criteria of the study. New treatments and changing algorithms in management may limit the relevance of the trial. Population-specific economic considerations may influence how study findings are incorporated into practice. New information that challenges an existing paradigm is oftentimes met with resistance.

The PTVT Study demonstrated that both tube shunt implantation and trabeculectomy with MMC are viable surgical options for managing medically uncontrolled glaucoma in patients without prior ocular surgery. With both glaucoma procedures, mean IOP was reduced to the low teens, and a majority of patients had an IOP of 14 mmHg or less throughout 5 years of follow-up [9,10,12■■]. This degree of IOP reduction is generally not seen with MIGS [17■]. Glaucoma surgical practice patterns are changing, and use of tube shunts has expanded beyond only refractory glaucoma [2–7]. The Tube Versus Trabeculectomy (TVT) Study showed that tube shunts were effective in treating glaucoma in a patient population at lower risk for surgical failure than had traditionally been relegated to this procedure [18]. The PTVT Study provides evidence that tube shunt placement is an appropriate primary incisional glaucoma procedure in low risk eyes.

Although the overall rate of surgical success was similar with both surgical procedures at 5 years, the rate of complete success was significantly higher after trabeculectomy with MMC compared with tube shunt placement [12■■]. This is consistent with the observed greater use of glaucoma medications with tube shunt surgery relative to trabeculectomy with MMC. These findings suggest that trabeculectomy with MMC is the preferred initial surgery in patients who are nonadherent or poorly tolerant of glaucoma medical therapy.

Baseline demographic and clinical features were explored as possible risk factors for treatment failure, and only lower preoperative IOP was significantly associated with failure in univariable and multivariable analyses [11■,12■■]. Patients with lower preoperative IOP benefited most from primary trabeculectomy with MMC, and patients with high preoperative IOP benefited most from primary tube shunt surgery in the PTVT Study. A post hoc analysis of TVT Study data similarly demonstrated that the efficacy of tube shunt surgery relative to trabeculectomy with MMC increases at higher levels of preoperative IOP [11■]. A risk factor analysis of pooled data from the Ahmed Baerveldt Comparison (ABC) Study, Ahmed Versus Baerveldt (AVB) Study, and tube group of the TVT Study also identified lower preoperative IOP as a significant predictor of tube shunt failure [19■■]. Given the influence of baseline IOP on the outcome of traditional glaucoma surgery, it should be considered when deciding between tube shunt surgery and trabeculectomy with MMC. Trabeculectomy allows titration of IOP postoperatively with laser suture lysis or releasable sutures, and this approach is particularly useful in patients with low preoperative IOP in which the surgeon is targeting a narrow IOP range postoperatively.

The PTVT Study showed that primary trabeculectomy with MMC is more effective in reducing IOP with a lower burden of medical therapy than primary tube shunt implantation [9,10,12■■]. However, trial results also indicate that the safety of tube shunt surgery may be better than trabeculectomy with MMC. Early complications were significantly more common after trabeculectomy with MMC compared with tube shunt placement [9,10,13■■]. Serious complications also developed more frequently following trabeculectomy with MMC than tube shunt surgery, although the difference was only statistically significant at 1 year. The ABC and AVB Studies similarly demonstrated that safety outcomes favored one randomized treatment arm (i.e., Ahmed implantation) while efficacy outcomes favored the other treatment arm (i.e., Baerveldt implantation) [20–22]. Unfortunately, a trade-off exists between safety and efficacy with all currently available glaucoma procedures. This is most apparent when comparing MIGS to traditional glaucoma surgery.

The recent introduction of MIGS has further diversified the surgical options available to glaucoma patients. These procedures appear to be associated with lower rates of surgical complications than trabeculectomy or tube shunt surgery, but they provide only modest IOP reduction [17■,23]. Selecting the most appropriate glaucoma procedure involves balancing the risks of complications and the benefit of IOP reduction for an individual patient. Surgeon skill and experience are important additional considerations when choosing a glaucoma operation that were not evaluated in the PTVT Study. Traditional glaucoma surgery will continue to play a role in the surgical management of glaucoma in the foreseeable future, especially among patients with advanced and/or progressive disease. The PTVT Study provides a wealth of information about trabeculectomy with MMC and tube shunt implantation to guide surgical decisions in similar patient groups.

KEY POINTS.

• The Primary Tube Versus Trabeculectomy (PTVT) Study is a multicenter randomized clinical trial comparing two commonly performed glaucoma procedures in eyes without previous incisional ocular surgery.

• Trabeculectomy with mitomycin C (MMC) and tube shunt implantation produced similar intraocular pressures after 5 years of follow-up, but few glaucoma medications were required after trabeculectomy.

• No significant difference in failure rate was observed between the two surgical procedures at 5 years.

• Early postoperative complications occurred more frequently after trabeculectomy with MMC compared to tube shunt surgery, but the rates of late postoperative complications and serious complications were similar with both procedures after 5 years.