aqueous shunts for the treatment of glaucoma

8/2/2019 Aqueous Shunts for the Treatment of Glaucoma

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TITLE: Aqueous Shunts for the Treatment of Glaucoma

AUTHOR: Jeffrey A. Tice, MD

Assistant Professor of Medicine

Division of General Internal Medicine

Department of Medicine

University of California San Francisco

PUBLISHER: California Technology Assessment Forum

DATE OF PUBLICATION: June 29, 2011

PLACE OF PUBLICATION: San Francisco, CA


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AQUEOUS SHUNTS FOR THE TREATMENT OF GLAUCOMA

A Technology Assessment

INTRODUCTION

The California Technology Assessment Forum (CTAF) was asked to assess the evidence for the use of

aqueous shunt devices for the treatment of glaucoma. Glaucoma is primarily treated with eye drops and

then laser therapy when eye drops fail. Surgical intervention, including the use of shunts, is usually reserved

for patients who fail therapy with eye drops and lasers.

BACKGROUND

Glaucoma

Glaucoma is the second most common cause of blindness in the United States and worldwide.1,2It is a

progressive optic neuropathy characterized by nerve atrophy and loss of retinal ganglion cells. In its most

common form, patients have progressive loss of peripheral vision that is usually asymptomatic even when it

is very advanced. As many as half of people with glaucoma are unaware that they have the disease. Signs

of disease include an elevated intraocular pressure (IOP), increased cup to disc ratio, and loss of vision on

formal peripheral field testing. Glaucoma is usually identified during routine eye examinations either by

noting an enlarged cup-to-disc ratio on fundoscopic examination, an increased IOP, or visual field loss with

perimetry.

There are several forms of glaucoma. The most common is open angle glaucoma, which is thought to be

due to resistance to flow through the trabecular network located at the angle formed by the iris and the

cornea in the anterior chamber of the eye. This leads to decreased drainage of aqueous humor into

Schlemms canal and a relatively increased IOP. Angle-closure glaucoma often presents acutely with a

painful red eye. It is characterized by a narrowed or closed anterior chamber angle, which limits drainage of

the aqueous humor. Other causes of glaucoma include vasoproliferative disease, pigment dispersion,

trauma, and uveitis.

Glaucoma is more common in older patients, African Americans, and those with a family history of


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glaucoma.1-9The primary modifiable risk factor for glaucoma is IOP, but up to 15% of patients with

glaucoma have normal IOP.4,10,11Normal IOP ranges from 10 to 21 mm Hg. Lowering IOP is the primary

therapy to limit or prevent vision loss. Several randomized trials and meta-analyses have demonstrated that

interventions to lower IOP lead to decreased vision loss over time.12-16Loss of vision from glaucoma can

have a significant impact on patients quality of life. Patients with glaucoma are at increased risk for falls and

motor vehicle accidents and it negatively impacts other activities of daily life.17-23

There is no single threshold pressure for beginning treatment.24Patients with normal IOP, but evidence of

optic disc cupping and visual field loss are usually recommended for treatment.25Treatment is usually

started for patients with IOP greater than 25 mm Hg, even in the absence of signs of early damage to the

optic nerve. Pharmacological therapy with eye drops is first line therapy. There are several classes of drops

including those intended to increase the outflow of aqueous humor (prostaglandins, alpha adrenergic

agonists, and cholinergic agonists) and those intended to decrease aqueous humor production (alphaadrenergic agonists, beta blockers, and carbonic anhydrase inhibitors).26There appears to be consensus

that the first class to be tried are the prostaglandins because they have fewer systemic side effects and are

at least as effective as the other classes of medications.27,28

When drugs fail, laser therapy (trabeculoplasty) is usually the next step. Either continuous wave or pulsed

lasers are directed at the trabecular network. Laser trabeculoplasty increases aqueous outflow and reduces

intraocular pressure, but its effectiveness decreases over time and repeated treatments are needed every

few years. It is a very safe procedure, with fewer side effects than either medications or surgery. It also has

been shown in one large randomized trial to be at least as effective as eye drops when used as the initial

therapy.29However, it becomes less effective with repeated treatments and many specialists do not use

laser trabeculoplasty more than two or three times on an individual eye.

Surgery is considered for patients who are inadequately controlled or intolerant of medical and laser

therapy. The history of glaucoma surgery dates back to the mid-19 th century.30The standard surgical

therapy today is trabeculectomy, also known as filtering surgery, in which part of the sclera is removed to

allow aqueous humor to drain in a controlled manner from the anterior chamber into the subconjunctival

space. The drainage region over the sclera is called a bleb. The surgery may fail over time due to excessive

healing (scar formation) at the drainage site, which increases resistance to the outflow of aqueous humor.

Anti-metabolite medications, such as mitomycin C and 5-fluorouracil, have been shown in randomized trials

to improve outcomes following surgical trabeculectomy, but they increase the risk for infection of the bleb

leading to endophthalmitis and also increase the risk for chronic hypotony and a large, uncomfortable bleb.

Both beta-irradiation and post-operative steroids have been used to control the healing process, but they


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have been abandoned in favor of the anti-metabolite therapies. Trabeculectomy surgery is associated with

uncommon, but severe complications, including endophthalmitis, cataract formation, and permanent

blindness, so it has traditionally been reserved for patients with glaucoma refractory to less invasive

treatments. The Collaborative Initial Glaucoma Treatment Study was a randomized trial that compared

trabeculectomy to medical therapy as the initial treatment for open angle glaucoma.31-34They found similar

visual field outcomes through five years of follow-up, but the surgical arm had higher early rates of visual

acuity deterioration. Subgroup analyses suggested that surgery may be preferred as the first line treatment

in patients presenting with advanced visual field defects, but that surgery led to worse outcomes in patients

with diabetes.33

Aqueous Shunts

Aqueous shunts are devices that, like surgical trabeculectomy, create an alternate path for aqueous humor

to leave the anterior chamber of the eye and thus lower IOP. They were initially used for patients who failed

medical and laser therapy and had an underlying diagnosis that increased the risk that surgical

trabeculectomy would fail. These conditions include neovascular glaucoma, uveitic glaucoma, corneal

transplant, and iridocorneal endothelial syndrome. However, recent trends suggest that they are being used

more often for patients at lower risk for trabeculectomy failure.35-38

There are a number of synonyms for aqueous shunts including glaucoma drainage devices, tube implants,

and tube shunts. Devices available in the United States include the Ahmed (12 models), Baerveldt (3

models), Krupin, Molteno (6 models), Optimed, or Schocket shunts. New devices include the SOLX Gold

shunt and the Ex-PRESS mini-shunt. The general approach of the shunts is to place a tube into the anterior

chamber of the eye that drains through a plate or multiple plates attached to the sclera. These shunts vary

in the materials used (silicone, silastic, polypropylene, gold, stainless steel), the use of valves in the tube,

and the size and number of plates. The tubes provide a conduit to allow the controlled flow of aqueous

humor from the anterior chamber to a space between the conjunctiva and the sclera (the bleb) where it is

absorbed into the blood.

The initial shunts were not valved and required a suture to be tightened around the drainage tube until

healing around the plate caused an increased resistance to flow. Without the suture, the IOP pressure

would drop too low (5 mm Hg or less) causing flattening of the anterior chamber, accelerated corneal

damage, and cataract formation, a condition known as hypotony. The suture is usually removed four to six

weeks after the initial surgery. Some newer shunts include a one-way valve or flow restrictor that limits flow

through the device when the pressure in the eye becomes low. This valved approach is intended to


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decrease the likelihood of post-operative hypotony and avoid the need for a second procedure to remove

the ligating suture, but has the potential to limit the long-term effectiveness of the shunt.

The Ex-PRESS shunt is a stainless steel device designed to have more reproducible results with less

dependency on surgical skills than other aqueous shunts. The initial subconjunctival implantation of the

device had a high complication rate, including erosion of the conjunctiva. This led to a modification of the

technique in which the shunt is implanted under a scleral flap.39

TECHNOLOGY ASSESSMENT (TA)

TA Criterion 1: The technology must have final approval from the appropriate government

regulatory bodies.

The FDA has approved the following aqueous shunt devices: Ahmed glaucoma valve implant(New worldMedical Inc.), Molteno implant (Molteno Ophthalmic Ltd.), Baerveldt glaucoma implant (Abbott Medical

Optics Inc.), Krupin-Denver vale implant (Hood Laboratories, Inc.), and Ex-PRESS Mini Glaucoma Shunt

(Alcon). The Solx DeepLight Gold Micro-Shunt (OccuLogix) and the EyePass Glaucoma Shunt are still in

Phase III of clinical trials and has not received FDA approval at this time.

TA Criterion 1 is met.

TA Criterion 2: The scientific evidence must permit conclusions concerning the effectiveness of

the technology regarding health outcomes.

The Medline database, Embase, Cochrane clinical trials database, Cochrane reviews database and the

Database of Abstracts of Reviews of Effects (DARE) were searched using the key words shunt, drain,

tube, device, implant, ahmed, baerveldt, krupin, molteno, optimed,schocket, express, or

solx. The results were crossed with the results from a search on glaucoma. The search was performed

for the period from 1945 through May 2011. The bibliographies of systematic reviews and key articles were

manually searched for additional references. References were also solicited from the manufacturers and

local experts. The abstracts of citations were reviewed for relevance and all potentially relevant articles were

reviewed in full. This review focuses on the randomized comparisons between aqueous shunts of different

designs and between the shunts and surgical trabeculectomy, the current standard surgical treatment.

There is an extensive observational literature documenting the feasibility and safety of lowering IOP with

aqueous shunts. However, outcomes clearly vary by patient characteristics including the underlying cause


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for glaucoma, the history and type of prior surgery, patient age, diabetes, and the presence of cataracts.

Randomized trials are essential to evaluate the comparative effectiveness of aqueous shunts, particularly

when there are many alternative therapies available.

The search identified 1214 potentially relevant studies (Figure 1). After elimination of duplicate and non-

relevant references including reviews and non-randomized studies the search identified 28 articles

describing 23 trials. The most important set of trials compare aqueous shunts to trabeculectomy, the current

standard for patients with an indication for an aqueous shunt. Additional randomized trials either evaluated

adjuncts to the standard shunt procedure or compared two different shunts.

Figure 1: Selection of studies for inclusion in review

Level of Evidence: 1 through 5.


1214 potentially relevant

references screened

227 abstracts for assessment

28 studies included inassessment:

23 randomized controlled trials(RCTs)

56 studies for full text review

513 duplicate citations excluded474 excluded: not randomized; reviews,

abstracts only; other interventions

171 studies excluded(Editorials, reviews, abstracts, no

clinical outcomes)

28 studies excluded: not randomized,no aqueous shunt arm


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TA Criterion 3: The technology must improve net health outcomes.

The most important outcomes for patients include preservation of vision (visual acuity, peripheral vision) and

quality of life. Secondary outcomes of importance include control of intraocular pressure and the number of

medications used to control IOP. Studies of glaucoma use a wide variety of definitions for success and

qualified success. Complete success is usually defined as an IOP 21 mm Hg and 6 mm Hg on no

medications a year following surgery. A qualified success is the same degree of pressure control, but on

medications. The World Glaucoma Association also suggests reporting results using two lower IOP cutoffs:

18 and 15 mm Hg.40Unfortunately, almost every trial used a slightly different definition for success and

failure making comparisons across trials problematic. The complications associated with aqueous shunts

include early hypotony, capsule fibrosis leading to increased IOP and thus clinical failure, visual loss, tube or

plate erosion, diplopia, strabismus, corneal decompensation, and infection.41,42

There are a large number of case series evaluating devices that shunt aqueous humor from the anterior

chamber of the eye to decrease IOP.43-55They demonstrate the long term safety and efficacy of Molteno

shunts for up to ten years47and the Ahmed device up to seven years.52,55There are also a number of

retrospective and prospective comparative studies.56-71Some evaluated variants in techniques for shunt

implantation60,61,66, some compared different shunt devices56,59,68,69,71, and others compared aqueous shunts

to trabeculectomy or other techniques for controlling IOP.57,58,63-65,67,70

The randomized trials are described in more detail below.

Technical approaches to aqueous shunt surgery

Several early randomized trials evaluated adjuncts to surgery to see if they improved outcomes. Valimaki

and colleagues randomized 22 patients undergoing implantation of a single plate Molteno shunt to treatment

with oral prednisolone for ten weeks in order to control bleb fibrosis.72Systemic corticosteroids did not

improve outcomes and are no longer used. Two other randomized trials evaluated the benefits of adding

mitomycin C to aqueous shunts, one with a Molteno shunt73and one with an Ahmed shunt.74Neither trial

found any benefit to the addition of mitomycin C and it is rarely used today. The Latin American Glaucoma

Society investigated the utility of performing a partial Tenons capsule resection when implanting an Ahmed

shunt for neovascular glaucoma.75Adding partial Tensons capsule resection did not improve outcomes or

reduce complications. Finally, there was one small trial that randomized twenty eyes to an Ahmed shunt

with or without pericardial membrane with a goal of reducing the post-operative hypertensive phase by

expanding the surface area of the endplate.76They found that expanding the endplate decreased the

incidence of the hypertensive phase to 20% compared to 80% in the control group (p=0.007) with a trend


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towards fewer patients requiring medications to maintain their target IOP.

Aqueous shunts versus surgical trabeculectomy

The observational data established that aqueous shunt devices could lower IOP with a reasonable

complication rate and that they are well tolerated in the eye for up to ten years. However randomized trials

are required to control for potential selection bias, measurement bias, and residual confounding in the

observational studies. Trabeculectomy is the accepted alternative treatment to lower IOP in the population

of patients refractory to medical and laser therapy. It is the ideal comparator for studies evaluating the

efficacy of aqueous shunts.

Ahmed Glaucoma Valve versus Trabeculectomy Study

The first randomized trial to compare an aqueous shunt device (Ahmed Model S-2) to trabeculectomy wasperformed in Sri Lanka and Saudi Arabia.77Some of the patients from the hospital in Sri Lanka were

included in a second study that reported three year outcomes.78In order to not count patients twice, this

technology assessment will primarily focus on the second study because it is larger and has a longer follow-

up. In brief, the first study found that participants in the Ahmed group had higher mean IOP and required

more glaucoma medications, but otherwise had similar results and complications.

The second study was performed at one site in Sri Lanka with all surgeries performed by one surgeon.

Patients with either primary open angle glaucoma or chronic angle closure glaucoma were eligible for

randomization. Exclusion criteria included other forms of glaucoma, prior intraocular surgery, lack of light

perception, age less than four years, and eyes requiring additional surgical interventions.

All patients were treated as randomized: 59 to the Ahmed group and 64 to the trabeculectomy group,

although the reported numbers differ in the two publications describing the study results. The mean age of

the participants was 52 years and 67% were female. The mean preoperative IOP was 25.9 mm Hg in the

Ahmed group and 26.9 mm Hg in the trabeculectomy group. None of the baseline characteristics differed

significantly between the two groups.

There were no significant differences between the two groups in visual fields or visual acuity at any of the

seven time points assessed except for improved visual field scores for the Ahmed group at two years. This

may have been a reflection of multiple statistical testing, but the trend favored the Ahmed group at every

time point. For the first year, IOP was higher in the Ahmed group, but the curves came together from 18

months through three years. From two to two and a half years, the average IOP was 13.1 mm Hg in the


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Ahmed group and 14.2 mm Hg in the trabeculectomy group. The cumulative probability of success during

the two to two and a half year time frame was 73.2% in the Ahmed group and 72.1% in the trabeculectomy

group.

Post-operative complications were similar in the two group (p>0.28 for each of the nine classes of

complications). The most common complications were a flat anterior chamber (15% in both groups),

hyphema (17% versus 11%,), corneal drying (14% versus 8%), and wound leak (3% versus 9%). Implant or

tube exposure occurred in 5% of patients in the Ahmed group. There were only two cases of persistent

hypotony and both occurred in the trabeculectomy group. There were nine repeat surgeries in each group.

The Ahmed group required repeat surgery for elevated IOP (n=4), repositioning of the tube (n=2), and

intervention for an exposed tube (n=3). The trabeculectomy group required repeat surgery for elevated IOP

(n=2), bleb revision (n=2), blebitis (n=1), and repair of a wound leak (n=4). Cataract surgery was performed

for 5 patients in the Ahmed group and 11 patients in the trabeculectomy group (p not reported).

In summary, the study demonstrated that the Ahmed shunt and trabeculectomy had equivalent preservation

of vision and control of IOP through two years with equivalent complication rates, though the types of

complications varied. However, the methodological quality of the study was questionable. A computer-

generated list of random numbers was used for group assignment, but apparently no allocation concealment

was used so selection bias cannot be ruled out. In addition, neither the surgeon nor the patients were

blinded, so measurement bias is possible. The use of mitomycin C in the trabeculectomy group was optional

and 9% of patients were not treated with the anti-metabolite therapy that is now standard. Follow-up was

incomplete as seven patients in the Ahmed group and six patients in the trabeculectomy group did not

return for follow-up after discharge from the initial hospitalization, and less than 50% of each group had

three years of follow-up. Larger, multicenter, multi-surgeon studies are needed to ensure the robustness of

these results.

Tube versus Trabeculectomy Study

The Tube versus Trabeculectomy (TVT) Study is a large, multicenter study comparing the safety and

efficacy of a non-valved aqueous shunt (Baerveldt 350 mm2) to surgical trabeculectomy with mitomycin C in

patients with prior intraocular surgery.79-84Patients were eligible for inclusion if they were between the ages

of 18 and 85 years, had inadequately controlled glaucoma with IOP 18 mm Hg and had undergone prior

surgery (trabeculectomy, cataract surgery, or both). Exclusion criteria included pregnancy, no light

perception, active proliferative retinopathy, recurrent uveitis, severe blepharitis, or the need for combined

surgery or additional ophthalmic surgical procedures. Randomization was stratified by clinical center and


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prior surgical type. Allocation concealment was not described. The primary outcome measure was IOP.

Important secondary outcomes were the rates of complications including bleb related infections and

persistent post-operative diplopia. Failure was defined as any of the following four criteria: IOP > 21 mm Hg

or not reduced by 20% on two consecutive follow-up visits; IOP 5 mm Hg on two consecutive follow-up

visits; additional glaucoma surgery; or loss of light perception. The outcome of complete success was

defined as a participant who did not fail and was not requiring supplemental medical therapy. Planned

follow-up is five years.

Between October 1999 and April 2004, the 17 study centers randomized 212 participants (n=107 to the tube

group; n=105 to the trabeculectomy group).83All participants received their assigned treatment. There were

no significant differences in age (mean 71 years), sex (53% female), race (45% White, 39% Black, 14%

Hispanic), or diabetes (32%). There were also no differences in the ocular characteristics of the participants

including the eye operated on (53% left), IOP (25.3 mm Hg), number of glaucoma medications (3.1), priorlaser therapy (52%), underlying diagnosis (81% primary open-angle glaucoma), or type of prior surgery

(44% prior cataract extraction, 56% prior trabeculectomy).

The one and three year results have been published81,82and the five year results should be available within

the next year. There were no significant differences in serious operative complications, though trends

favored the tube group. Intraoperative complications tended to be less common in the tube group (7%

versus 10%, p=0.59). Significant post-operative complications in the first year, defined as those requiring

reoperation and/or a loss of at least two lines of visual acuity on a Snellen chart, also tended to be less

common in the tube group (17% versus 27%, p=0.12). Post-operative complications were significantly less

common in the tube group (34% versus 57%, p=0.001), but most of these were self-limited. Two individual

complications were significantly less common in the tube group: corneal dysesthesia (1% versus 7%,

p=0.034) and wound leaks (1% versus 11%, p=0.004). There was a trend toward more persistent diplopia in

the tube group (5% versus 0%, p=0.06). A new or worsened motility disturbance of the eye (strabismus) was

more common in the tube group (9.9% versus 0%, p=0.005).84At one year there was no difference in IOP

(12.4 mm Hg in tube group versus 12.7 in the trabeculectomy group, p=0.73), but the average number of

glaucoma medications used was higher in the tube group (1.3 versus 0.5, p


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At three years there was also no difference in IOP (13.0 mm Hg in tube group versus 13.3 in the

trabeculectomy group, p=0.78) and the average number of glaucoma medications used was no longer

significantly higher in the tube group (1.3 versus 1.0, p=0.30). Significant post-operative complications

through three years also did not differ between the two groups (22% versus 27%, p=0.58). Complete

success was less common in the tube group (28% versus 40%, p = 0.10). However, failures were also less

common in the tube group (15.1% versus 30.7%, p=0.010). At three years, the reasons for failure were

inadequate IOP control (7 in tube group, 10 in trabeculectomy group), persistent hypotony (2 in tube group,

8 in trabeculectomy group), reoperation for glaucoma (6 in tube group, 9 in trabeculectomy group), and loss

of light perception (0 in tube group, 1 in trabeculectomy group). Although none of the subgroup differences

were statistically significant, the trend favored the tube group in all subgroups.

The TVT study is the largest randomized trial to directly compare an aqueous shunt tube to surgical

trabeculectomy. Follow-up was excellent with only 10% of visits missed during three years of follow-up. Allpatients received their allocated treatment and strict intention-to-treat was used for all analyses.

Methodologically, it was not perfect because the participants and providers were not blinded, which may

have biased the assignment of complications and the decision to reoperate. However, measurement bias in

studies with objective outcomes tends to be less significant than in studies with subjective outcomes.85In

response to this criticism, the investigators published data demonstrating a trend in the opposite direction:

the mean IOP at the time of reoperation was 21.5 mm Hg in the tube group and 27.9 mm Hg in the

trabeculectomy group (p=0.12).

When comparing the results of the TVT study to other studies, it is important to keep in mind the population

studied. All of the participants in the TVT study had undergone at least one prior ocular surgery, but patients

with conditions predisposing them to surgical failure (neovascular glaucoma, iridocorneal endothelial

syndrome) were excluded. Thus, patients were at higher risk for complications than surgically nave

patients, but at lower risk than many of the patients included in the early case series and comparative

studies of aqueous shunts, which often included patients at high risk of failure following trabeculectomy.

Both operations continue to evolve. In the TVT study, trabeculectomy was performed using a limbus-based

conjunctival flap. Recent trends suggest that trabeculectomy performed using a fornix based flap with

diffuse rather than focal application of mitomycin C may be preferred.86In addition, only one type of

aqueous shunt was used: the Baerveldt 350. Many other devices are in use or in development. The results

of the TVT study may not generalize to other aqueous shunts.

Through three years, participants randomized to the Baerveldt aqueous shunt group had fewer short-term


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complications (34% versus 57%), fewer failures (15% versus 30%), but more diplopia (5% versus 0%) and

more strabismus (9.9% versus 0%). The failure rate in the tube group was lower than that estimated by a

recent meta-analysis41, but the patients randomized came from a lower risk group. Overall, the evidence

from the TVT study suggests that the Baerveldt aqueous shunt is at least equivalent to trabeculectomy in

this patient population.

Ex-PRESS versus Trabeculectomy

Several case series reported that the Ex-PRESS shunt, a newer stainless steel aqueous shunt, was safe

and effective at lowering IOP44,45,49,50,53except when performed using the older, subconjunctival technique.54

Additional comparative studies suggest that the lowering of IOP and the reduction in use of glaucoma

medications achieved with the Ex-PRESS shunt were equivalent to trabeculectomy with fewer complications

(hypotony, choroidal effusion, hyphema).57,58,64,67,87The two randomized trials comparing the Ex-PRESS

device to trabeculectomy are described below.88-90

In this single center study by a single surgeon, 80 eyes from 78 patients were randomized to either the Ex-

PRESS shunt or trabeculectomy.90Patients were eligible for the study if they were ages 18 and older with

open angle glaucoma that was inadequately controlled with medical therapy. Exclusion criteria included any

other ocular disease and previous ocular surgery other than cataract extraction. Complete success was

defined as a final IOP > 4 mm Hg and 18 mm Hg without medication. Overall success was defined by the

same criteria with or without medication. Failure was an IOP > 18mm Hg or the need for additional

glaucoma surgery. The more typical definition of failure (recurrent surgery, loss of 2 lines of Snellen visual

acuity; or IOP out of range) was not reported for either group.

There were 40 eyes in each group. The Ex-PRESS group was significantly younger (62.3 years versus 68.9,

p=0.03) and there was a trend towards more female participants in the Ex-PRESS group (52.5% versus

32.5%, p= 0.11). The mean preoperative IOP was 22.8 mm Hg in the Ex-PRESS group and 21.5 mm Hg in

the trabeculectomy group (p=0.34). There were no significant differences in IOP at one year (approximately

12 mm Hg in the Ex-PRESS group and 13 mm Hg in the trabeculectomy group) or in the number of

medications used (0.3 versus 0.6, p not reported except non significant). The proportion of patients

achieving an IOP 18 mm Hg at one year was greater in the Ex-PRESS group (84.6% versus 60%,

p=0.023). However, the success rate with or without medications did not differ between the two groups (97%

versus 87%, p=0.20). Visual acuity declined in 13.5% of patients in the Ex-PRESS group who returned for

the one year visit and in 15.8% of the trabeculectomy group (p not significant). There were 13 complications

in the Ex-PRESS group (32.5%) and 11 complications in the trabeculectomy group (27.5%). Early hypotony


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with a shallow anterior chamber was the most common complication. Complications requiring surgical

intervention were identical (5% in each group).

The five-year results demonstrated continued good control of IOP in both groups (11.5 versus 11.3 m Hg, p

NS). There were no significant differences between the groups in the percentage of patients with successful

control of IOP ( 18 mm Hg) without medications (59% versus 46%, p=0.25) or with medications (97.4%

versus 100%, p=0.49). The use of glaucoma medications was similar in the two groups at five years (0.85

versus 1.10, p not reported), but the number was increasing in the Ex-PRESS group, while decreasing in

the trabeculectomy group. The Ex-PRESS group experienced fewer complications requiring needling (3

versus 9) and fewer cataract surgeries (5 versus 8), but no statistical analysis was reported. No data on

repeat glaucoma surgeries or loss of vision were reported. There was also no reporting of any loss to follow-

up or deaths.

There are many methodological issues with this trial. It was a relatively small trial, so estimates of event

rates would have wide confidence intervals. In addition, the confidence intervals were not reported. As in

most trials of aqueous shunts, there was no blinding of the investigator or the patients, which may have

introduced some bias in decisions about medication use or other interventions. The significant baseline

differences in age and sex call into question concealment of the randomization sequence generated by the

computer. Only a handful of baseline characteristics were reported in Table 1 and follow-up was

incompletely reported. Because a single surgeon performed all procedures in this study, the results may

reflect his personal skill set and may not be generalizable beyond his practice. This study suggests that the

Ex-PRESS device may be equivalent to trabeculectomy in the population studied for at least five years, but

a larger multicenter study with better reporting is required in order to convincingly demonstrate that

conclusion.

The second trial randomized 30 eyes from 15 patients to either the Ex-PRESS shunt or to trabeculectomy

and followed for an average of 24 months.88Patients over the age of 18 years with primary open angle

glaucoma who required bilateral surgical treatment were eligible. Patients with other forms of glaucoma and

active uveitis were excluded. One surgeon performed all of the procedures. Complete success was defined

as IOP > 5 mm Hg and < 18 mm Hg without glaucoma medications. The average age of the participants

was 65 years, 33% were female, 40% Black, 33% Indian, and 20% Caucasian. The baseline IOP was 28.1

mm Hg in the Ex-PRESS group and 31.1 mm Hg in the trabeculectomy group (p=0.48) with an average of

3.7 medications used by each group. Prior surgeries for glaucoma had been performed on 67% (10/15) of

the eyes in each group. One patient died after 13 months of follow-up and two were lost to follow-up. IOP

decreased to 15.7 mm Hg in the Ex-PRESS group and to 16.2 mm Hg in the trabeculectomy group (p NR).


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Post-operative use of glaucoma medications were similar (0.3 versus 0.9, p NR). The complete success rate

was greater in the Ex-PRESS group (~77% versus ~28% estimated from Kaplan-Meier plot at 24 months,

p=0.002). Complications were less common in the Ex-PRESS group (20% versus 33%, p=0.05) as were

complications requiring surgical intervention (0% versus 27%, p=0.001). The most common complication

was hypotony (7% Ex-PRESS group, 33% trabeculectomy group), but all resolved spontaneously and

without serious complication within one month of surgery.

In this small, single surgeon randomized trial, the Ex-PRESS shunt showed a reduction in IOP similar to that

achieved with trabeculectomy, but with fewer complications and fewer patients requiring medications to

maintain target IOP.

Randomized trials comparing devices

Single-plate versus double-plate Molteno shunt

One of the earliest randomized trials of aqueous shunt devices compared the single-plate Molteno shunt to

the double-plate Molteno shunt to evaluate whether the greater surface area of the double endplant

improved outcomes through a greater reduction in IOP.91Between March 1988 and February 1990, the

study randomized 132 patients who had a poor surgical prognosis with trabeculectomy. The average pre-

operative IOP was 34.8 mm Hg. Allocation concealment was preserved until the patient was in the

operating room. The primary outcome was IOP 21 mm Hg and 6 mm Hg with no additional glaucoma

surgeries and no devastating complications. At one year, the success rate was 55% in the single-plategroup and 86% in the double-plate group. At two years, the success rate was 46% in the single-plate group

and 71% in the double-plate group. The difference in success rates between groups was statistically

significant (p=0.0035). The average reduction in IOP was 25% for the single-plate group and 46% for the

double-plate group (p=0.01). Visual acuity loss of at least two Snellen lines was also more common for the

single-plate group (27% versus 20%, p NR). There was less post-operative hypotony in the single-plate

group resulting in fewer flat anterior chambers (4% versus 10%, p=0.25) and fewer choroidal hemorrhages

or effusions (0% versus 8%, p=0.043). The remaining complications were uncommon and there were no

significant differences between the groups, but the difference favored the single-plate shunt.

In summary, the increased surface area of the double-shunt increased the success rate in patients with poor

surgical prognosis. However, there was also an increase in early hypotony and other complications. Surgical

techniques and medical therapy have evolved significantly in the twenty years since the study was

performed, so the results may not apply today.


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Double-plate Molteno versus Schocket Procedure

Another early randomized trial of aqueous shunt devices compared the double-plate Molteno shunt to the

anterior chamber tube shunt to encircling band (ACTSEB) procedure developed by Schocket.92This was a

small randomized trial of 40 eyes with all procedures performed by a single surgeon between 1987 and

1989. Post-operative IOP at two years was similar in the two groups (14.4 mm Hg Molteno, 15.0 mm Hg

ACTSEB,p=0.74), but the Molteno group required more medications (0.95 versus 0.43, p=0.024). Surgical

interventions for complications or inadequate IOP control was high in both groups, but less common in the

Molteno group (47% versus 57%, p NR). Visual acuity decreases of two lines or more on the Snellen chart

were also less common in the Molteno group (32% versus 52%, p NR). These results may reflect the skills

of a single surgeon and the number of eyes randomized was low, so the results may not be generalizable.

Furthermore, the surgeries were performed more than 20 years ago: medical therapy, surgical techniques

and the devices have changed significantly in the interim. In view of these limitations, this trial suggests thatthe Molteno shunt provides equivalent control of IOP to that of ACTSEB with at least a trend towards fewer

complications and less loss of vision.

Baerveldt 350 versus Baerveldt 500

A larger study randomized 107 patients between 1991 and 1993 to the Baerveldt shunt with a 350 mm2

endplate or a 500 mm2 endplate.93,94The goal was to evaluate whether the greater surface area led to

greater reductions in IOP and higher long-term success rates similar to those reported in the single-plate

versus double-plate Molteno trial.91The average pre-operative IOP was 30.5 mm Hg. Success was defined

as IOP 21 mm Hg and 6 mm Hg with or without additional medication. Failure was defined as IOP > 21

mm Hg on two consecutive visits, additional glaucoma surgery, loss of light perception or IOP < 6 mm Hg.

At one year, the success rate was 98% in the 350 mm2 group and 92% in the 500 mm2 group. At two years,

the success rate was 93% in the 350 mm2 group and 75% in the 500 mm2 group. Even though the median

follow-up was only about 36 months, the investigators reported results out to five years. At five years, the

success rate was 79% in the 350 mm2 group and 66% in the 500 mm2 group. The difference in success rate

was statistically significant at all time points. The overall failure rate was 13% in the 350 mm2 group and

30% in the 500 mm2 group (p=0.05). The mean IOP at 2 years was 13.2 mm Hg in the 350 mm2 group and

12.3 mm Hg in the 500 mm2 group (p=0.41). Visual acuity loss of at least two Snellen lines was similar in the

two groups (50% versus 54%, p 69). There were no significant differences in the complication rates between

the two groups during any year of follow-up, though there were slightly more complications in the 500 mm2

group.


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This study found that the 350 mm2 Baerveldt shunt had a greater success rate through five years of follow-

up with a trend towards fewer complications and fewer failures. As with the prior studies, this study was

performed almost 20 years ago, so the results may not generalize. However, it clearly demonstrated that

there was no advantage to increasing the area of the endplate beyond 350 mm2. Of note, the Molteno single

plate device had an area of approximately 130 mm2 and the double plate had an area of 270 mm2.

The Ahmed Baerveldt Comparison Study

The recently published early results from the Ahmed Baerveldt Comparison (ABC) Study are important

because they allow for direct evaluation of the comparative effectiveness of a valved aqueous shunt

(Ahmed) and a non-valved aqueous shunt (Baerveldt 350) in the modern era of glaucoma management.95,96

The size of the end plate is another major difference between the two devices (184 mm2 for the Ahmed

Device and 350 mm2 for the Baerveldt device), so the trial is not strictly a comparison between a valved and

non-valved device. Prior observational studies have not conclusively defined the relative benefits and harms

of the two devices.59,68,71,97,98They are the two most commonly used aqueous shunts in the United States

and glaucoma surgeons divided in their opinion about the preferred device.96

Patients were eligible for inclusion in the ABC study if they were between the ages of 18 and 85 years, had

inadequately controlled glaucoma with IOP 18 mm Hg and had an aqueous shunt as their planned

surgery. Exclusion criteria included lack of light perception, prior aqueous shunt implantation, prior

cyclodestructive procedure, uveitis associated with systemic illness like juvenile rheumatoid arthritis, the

need for combined surgery or additional ophthalmic surgical procedures, or if they lived at a distance and

would be unavailable for follow-up. Randomization was stratified by surgeon within clinical center and type

of glaucoma. Allocation concealment was not described. The primary outcome measure was the success

rate where success was defined as not failing. Failure was defined as any of the following five criteria: IOP >

21 mm Hg or not reduced by 20% on two consecutive follow-up visits; IOP 5 mm Hg on two consecutive

follow-up visits; additional glaucoma surgery; removal of the implant; or loss of light perception. The sample

size for the study was based on the results from a comparative study in Singapore that reported a 67%

success rate for the Ahmed shunt and an 83% success rate for the Baerveldt shunt.98Important secondary

outcomes were the rates of complications including hypotony, tube occlusion, macular edema,

endophthalmitis, cataract, diplopia, corneal edema, and tube or shunt erosion. Planned follow-up is five

years.

Between October 2006 and April 2008, 16 centers randomized 286 participants, but ten participants

withdrew consent prior to surgery. The publications only report data on the remaining 276 participants


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(n=143 in the Ahmed group; n=133 in the Baerveldt group).95Two participants in each of the groups

received a device other than their assigned treatment. However, all analyses were performed according to

randomization in adherence with strict intention-to-treat principles. There were no significant differences in

age (mean 64 years), sex (49% female), race (49% White, 25% Black, 12% Hispanic, 12% Asian), or

diabetes (41%). There was a trend towards older participants in the Ahmed group (65 versus 62 years,

p=0.053) and significantly more patients with hypertension in the Ahmed group (63% versus 50%, p=0.039).

There were also no differences in the ocular characteristics of the participants including the eye operated on

(46% left), IOP (31.5 mm Hg), number of glaucoma medications (3.4), or the underlying diagnosis (40%

primary open-angle glaucoma, 29% neovascular, 7% uveitic, 7% primary angle closure glaucoma, 18%

other).

The one year results have been published.96The three and five year results should be published in the

future. There were no significant differences in intraoperative complications, though trends favored theAhmed group (8% Ahmed versus 11% Baerveldt, p=0.31). Intraoperative complications were primarily of

hyphemas (22/28 = 79%). Significant post-operative complications in the first year, defined as those

requiring reoperation and/or a loss of at least two lines of visual acuity on a Snellen chart, also tended to be

less common in the Ahmed group (20% versus 34%, p=0.12). Any early post-operative complication in the

first three months was also less common in the Ahmed group (43% versus 58%, p=0.016), but most of

these were self-limited. Two individual complications were significantly less common in the Ahmed group:

corneal edema (12% versus 22%, p=0.035) and tube occlusion (2% versus 9%, p=0.015). Diplopia was

similar in the two groups (6% versus 5%, p=0.80) as were tube erosions (1 in each group). At one year IOPwas higher in the Ahmed group than the Baerveldt group (15.4 mm Hg versus 13.2, p=0.007), and the

average number of glaucoma medications also tended to be higher in the Ahmed group (1.8 versus 1.5,

p=0.071). The rate of failures at one year was similar using the primary outcome definition of failure as an

IOP > 21 mm (16.4% versus 14%, p=0.017). The reasons for failure in the Ahmed group were inadequate

IOP control (n=20) including 11 who required reoperation, loss of light perception (n=2), but no one with

persistent hypotony. The reasons for failure in the Baerveldt group were inadequate IOP control (n=7),

including 1 who required reoperation, loss of light perception (n=6), and persistent hypotony (n=2). The one

year failure rate was significantly higher in the Ahmed group for the strictest definition of failure: IOP > 14mm Hg (38.6% versus 24.0%, p=0.008).

Thus, through one year of follow-up, there is no clearly preferred aqueous shunt. Participants in the

Baerveldt group had lower IOP, tended to need fewer medications, had fewer reoperations for inadequately

controlled IOP, and tended to have fewer failures, but they also had significantly more serious complications

and significantly more reoperations for complications. The results from continued follow-up through three to


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the planned five years will better define the comparative effectiveness of these two devices.

Ahmed versus Molteno

There is one additional recent comparative trial, though it is relatively small and had poor follow-up.

Between 2003 and 2005, the study randomized 92 patients from three centers in Iran to the Ahmed shunt or

the Molteno single-plate shunt. Patients with poorly controlled IOP despite maximally tolerated medications

or who had failed prior surgery were eligible for randomization. The exclusion criteria were age less than 40

years, no light perception, cataracts, prior drainage device implantation, prior cyclodestructive surgery,

active ocular infection, or immunosuppression. The primary outcome measure was IOP. Failure was defined

as IOP > 21 mm Hg on two consecutive visits, additional glaucoma surgery, shunt removal, loss of light

perception, any major complication, or IOP < 6 mm Hg.

The study sample had a mean age of 61 year, 49% were female, and the pre-operative IOP was 32 mm Hg.

There were no significant differences between the two groups at baseline. Follow-up was poor: only 75% of

the sample were available for analysis at one year and only 62% were available at two years. At two years,

the mean IOP was higher in the Ahmed group (17.0 versus 15.4, p


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TA Criterion 4: The technology must be as beneficial as any established alternatives.

Surgical trabeculectomy with either mitomycin C or 5 flurouracil is the current established alterative to which

other surgical procedures, like aqueous shunts, are usually compared. The risk of infection

(endophthalmitis) following trabeculectomy with anti-fibrotic agents is approximately 1% per year99and

severe central vision loss is reported in up to 6% of surgically treated eyes.100The Tube versus

Trabeculectomy study directly addresses the question of whether aqueous tube shunts are as beneficial as

trabeculectomy in a population of patients with glaucoma who had previously had ocular surgery. Through

three years, the patients who were randomized to the aqueous tube shunt (Baerveldt 350) had fewer

complications and fewer failures, while maintaining equivalent control of IOP. Patients in the shunt group

had a higher incidence of diplopia (5%) and strabismus (10%). The study was adequately powered and had

very little loss to follow-up, but neither the patients nor the investigators were blinded. The study will

continue to report outcomes through five years, but the overall conclusions are unlikely to change.

Observational studies through ten years of follow-up have not identified a significant increase in the risk for

failure of aqueous shunts47,52,55, though the efficacy of both aqueous shunts and trabeculectomy continues

to wane with time.

The TVT study study investigated one of the most highly studied aqueous shunts, the Baerveldt 350 mm2

shunt. It is unclear whether other shunts are equally effective. However, the ABC study96compared the

Ahmed shunt to the Baerveldt 350 shunt and reported similar outcomes at one year. The Ahmed shunt had

slightly fewer complications, but controlled IOP slightly less effectively. It will be important to watch the long-

term results of this study. For now, the evidence supports rough equivalence of the two devices, though the

balance of benefits and harms differ and may influence the choice of which device to use based on

individual patient characteristics.

The data for the Ex-PRESS shunt are less robust. There are two single surgeon randomized trials that

reported equivalent outcomes to trabeculectomy for up to five years with lower complication rates, but the

quality of the reporting in the trials and some methodological concerns decrease confidence in the results.88-

90 The total number of patients randomized in the two Ex-PRESS trials is less than half the number in the

TVT trial. However, the low complication rate and in the context of the results from the TVT and ABC

studies, the Ex-PRESS shunt appears to be equivalent to the existing standard. A randomized trial directly

comparing the Ex-PRESS shunt to one of the more commonly used aqueous shunts, like the Baerveldt 350,


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would better define the balance of benefits and harms with the Ex-PRESS shunt and help surgeons

individualize treatment decisions for their patients.


TA Criterion 5: The improvement must be attainable outside of the investigational setting.

Surgery to implant aqueous shunts is technically difficult and has an important learning curve. However, the

procedure has been successfully performed in multiple centers by multiple surgeons in multi-center trials,

like the TVT Study82and the ABC study96, and have been used in clinical practice for more than twenty

years. The results demonstrated in those two randomized trials should be attainable outside the

investigational setting. The one exception is the Ex-PRESS shunt. The two trials demonstrating equal orbetter outcomes compared to trabeculectomy both were single surgeon studies. The results in those trials

may reflect the individual surgeons expertise and may not be attainable in other settings. However, the

device was designed to be easier to implant than other aqueous shunts and was performed with similar

complication rates as trabeculectomy by residents in a training program.67


CONCLUSION

Glaucoma is the second leading cause of blindness worldwide after cataracts. The pathophysiology of

glaucoma remains incompletely understood, but lowering IOP has been demonstrated to slow the

progressive loss of peripheral and central vision that are the hallmarks of the disease. Medical therapy and

laser therapy for glaucoma have improved over the past thirty years, but a substantial portion of patients

with glaucoma continue to progress in spite of maximally tolerated non-invasive therapy. Surgical

trabeculectomy has been the established therapy for this group. However, trabeculectomy carries with it

short term risks for worsening vision or blindness, long term risks for ocular infections, and a tendency to fail

over time, particularly for patients with glaucoma associated with neovascular disease, uveititis, or

iridocorneal endothelial disease.

Aqueous shunts were developed as an alternative to trabeculectomy. Initially, they were used for patients

who had failed trabeculectomy and for patients with diseases known to have a poor outcome with


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trabeculectomy. A large number of randomized trials evaluating aqueous shunts have been published, but

many were small and focused on technical aspects of the surgery. Early trials established that larger

endplates lead to better IOP control, but that very large endplates increase the risk for complications without

additional clinical benefits. Two recent trials have had the largest impact on clinical practice and are the

most important to focus on when deciding whether aqueous shunts meet CTAFs TA criteria. The Tube

versus Trabeculectomy study was a multicenter trial that randomized 212 patients who had undergone prior

ocular surgery to either the Baerveldt 350 mm2 shunt or surgical trabeculectomy. Through three years of

follow-up the two procedures had similar rates of IOP control, vision loss, cataract progression, and

reoperations. However, patients in the Baerveldt tube group had a lower rate of complications and a lower

failure rate. This study demonstrated that net outcomes with the Baerveldt aqueous shunt were at least

equivalent to those achieved by trabeculectomy in patients who had undergone prior surgery.

The ABC study randomized 286 patients to one of two popular aqueous shunts, the Ahmed and theBaerveldt 350 mm2. Through one year of follow-up outcomes were similar in the two groups, though there

was a trend towards fewer complications in the Ahmed group and better IOP control in the Baerveldt group.

Although the overall outcomes are similar to date, the relative mix of benefits and harms may guide a

surgeon in choosing one device over another. Additional results from this study extending the results from

one year out to five years of follow-up will be forthcoming.

The data supporting the Ex-PRESS shunt are less robust. There are two small randomized trials comparing

the device to trabeculectomy. Both were single surgeon studies and one involved only 30 eyes in 15

patients. The results suggest that the Ex-PRESS shunt has similar success rates as trabeculectomy, but

lower rates of complications. This literature would benefit from a large trial comparing the Ex-PRESS shunt

to one of the aqueous shunts that has been well studied, like the Baerveldt 350.

RECOMMENDATION

It is recommended that use of aqueous shunts for the treatment of glaucoma not adequately controlled by

medication and / or laser therapy meets CTAF TA Criterion 1 through 5 for safety, effectiveness and

improvement in health outcomes.

The California Technology Assessment Forum panel voted to accept the recommendation as

written.

.


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June 29, 2011

This is the first review of this technology by the California Technology Assessment Forum.

RECOMMENDATIONS OF OTHERS

Blue Cross Blue Shield Association (BCBSA)

The BCBSA Technology Evaluation Center has not conducted an assessment of aqueous shunts for the

treatment of glaucoma.

Centers for Medicare and Medicaid Services (CMS)

CMS does not have National Coverage Determination for glaucoma drainage devices. Coverage decisions

are left up to the discretion of local Medicare and Medicaid carriers.

The American Academy of Ophthalmology (AAO)

The American Academy of Ophthalmology provided an opinion on this technology. No AAO representative

provided testimony at the meeting

The American Glaucoma Society

The American Glaucoma Society did not provide an opinion on this technology. No representative provided

testimony at the meeting.


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ABBREVIATIONS

CTAF California Technology Assessment Forum

IOP Elevated intraocular pressure

DARE Database of Abstracts of Reviews of Effects

RCT Randomized Controlled Trial

TVT Tube versus Trabeculectomy

NS Not significant

CI Confidence Interval

ACTSEB Anterior chamber tube shunt to encircling band

NR Not reported

ABC Ahmed Baerveldt Comparison


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aqueous shunts for the treatment of glaucoma

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