**Background**

Primary open-angle glaucoma (POAG) has a prevalence in the US of 2% of adults
over 40 years old, or about 2.2 million people and is expected to increase to
3.3 million in 2020 as the population ages.1 POAG is a chronic, progressive
optic neuropathy in adults in which there is a characteristic acquired atrophy
of the optic nerve and loss of retinal ganglion cells and their axons. It is
associated with an increased intraocular pressure (IOP) due to a buildup of
aqueous fluid within the eye which can lead to visual field loss and optic
nerve damage, usually without any associated pain or discomfort. The increased
IOP is secondary to an imbalance between aqueous fluid secretion and fluid
outflow despite an open angle. Nearly 40% of those with otherwise
characteristic POAG may not have elevated IOP measurements.1  
  
In the primary (conventional) outflow pathway from the eye, aqueous humor
passes through the trabecular meshwork, enters a space lined with endothelial
cells (Schlemm's canal), drains into collector channels and then into the
aqueous veins. Increases in resistance in the trabecular meshwork or the inner
wall of the Schlemm's canal can disrupt the balance of aqueous humor inflow
and outflow, resulting in an increase in IOP and glaucoma risk.  
  
The goal in POAG is to reduce the IOP to slow the development of optic nerve
damage. The IOP can be reduced by medical treatment or surgery, alone or in
combination. IOP above 21 mmHg has been shown to increase rates of visual
field loss. However, because of the differences in susceptibility to pressure-
related disc damage among POAG patients, pressure-lowering treatments are
aimed at achieving a lower "target" pressure individualized to each patient's
baseline IOP in which glaucomatous damage occurred.  
  
When the maximum tolerated medical therapy fails to control progression of
glaucomatous optic neuropathy, surgical care is considered the next treatment
option. Traditional filtration surgery includes trabeculectomy (including
Express shunt) and aqueous drainage implants (Ahmed, Baerveldt, Molteno).
Trabeculectomy uses the patient's own sclera to create a fistula to the
subconjunctival space over the sclera. Aqueous drainage implants use
silicone/plastic tubing and large plates to shunt aqueous humor to the
subconjunctival space in the equatorial region of the eyeball.  
  
While IOP outcomes are generally worse with aqueous drainage implants compared
with trabeculectomy, complications such as hypotony (low pressure) and
postoperative infection are reduced. However, failure rates are similar
(approximately 10% of devices fail annually) and shunts still have
complications, including corneal endothelial failure and erosion of the
overlying conjunctiva.  
  
The term micro-invasive or minimally invasive glaucoma surgery (MIGS) refers
to a group of newer surgical procedures that are performed by using an ab
interno (from inside the eye) approach via gonioscopic guidance and involve
minimal trauma to ocular tissues. In contrast to external filtration surgeries
such as trabeculectomy and aqueous tube shunt, these procedures are
categorized as internal filtration surgeries. Compared with traditional
filtration surgery, MIGS holds the promise of faster recovery time and less
severe complications.  
  
It is this potentially improved safety profile that opened up the indications
for MIGS to include patients with early-stage glaucoma to reduce the burden of
medications and problems with compliance (due to eye drop application
difficulty, cost, cosmetic effects and frequency). Another area of
investigation is patients with glaucoma who require cataract surgery. An
advantage of ab interno shunts is that they may be inserted into the same
incision and at the same time as cataract surgery. In addition, most devices
do not preclude subsequent trabeculectomy if needed. Therefore, health
outcomes of interest are the IOP achieved, reduction in medication use,
ability to convert to trabeculectomy, complications and device durability.  
  
There are 4 Food and Drug Administration (FDA) approved/cleared micro-invasive
surgical stents, [the iStent Trabecular Micro-Bypass Stent
](https://www.accessdata.fda.gov/cdrh_docs/pdf8/P080030A.pdf)(2011), the [XEN
Glaucoma Treatment System
](https://www.accessdata.fda.gov/cdrh_docs/pdf16/K161457.pdf)(November, 2016),
the [Hydrus Microstent System
](https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170034C.pdf)(August 2018)
and the [iStent _inject_
](https://www.accessdata.fda.gov/cdrh_docs/pdf17/P170043C.pdf) (June 2018).
The CyPass Micro-Stent System was recalled in September 2018 for safety
reasons. The iStent is a small (1 mm x 0.5 mm) L-shaped titanium device that
is inserted into Schlemm's canal to augment the natural outflow system. The
XEN45 is a 6 mm long porcine-derived gelatin stent inserted into the
subconjunctival space bypassing the natural outflow system. The iStent _inject
_ system comprises 2 heparin-coated titanium stents (each having 0.23 mm
diameter x 0.36 mm height, 0.08 mm central lumen diameter, and 4 0.05 mm side
outlets to allow for multidirectional outflow), both inserted into Schlemm's
canal using a pre-loaded auto-injection trocar. Hydrus is a 8 mm nitinol,
crescent-shaped microstent with alternating spines for support and windows to
provide outflow, also placed into Schlemm's canal.

The iStent, iStent _inject_ , and Hydrus are FDA approved for use in
combination with cataract surgery to reduce IOP in adults with mild or
moderate open angle glaucoma (OAG) and a cataract that are currently being
treated with medication to reduce IOP. XEN45 was granted FDA clearance for
the management of refractory glaucoma, including cases where previous surgical
treatment has failed, cases of POAG and pseudoexfoliative or pigmentary
glaucoma with open angles that are unresponsive to maximum tolerated medical
therapy. The pivotal trial data for each, constituting the main evidentiary
support, is summarized in the table below.  
  
Pivotal Trials for FDA Approved Micro-Invasive Glaucoma Surgery*

Study | Year | Journal | FDA | Study Design | No. of Eyes | Follow-up (yrs) |
IOP  21mm Hg no Meds |  IOP 20% no meds | Mean # meds | Mean IOP reduction
(mm Hg) | Conclusions  
---|---|---|---|---|---|---|---|---|---|---|---  
Samuelson, iStent Study Group3 | 2011 | Ophthalmology | PMA | RCT | 111/122 |
1 yr. (233) | 72%/50% (p>0.001) | 66%/48% (p=0.003) | 0.2/0.4 (p=0.011) |
8.4/8.2 (p=NS) | Pressure reduction on fewer medication was clinically and
statistically significantly better 1 year after stent plus cataract surgery
versus cataract surgery alone, with an overall safety profile similar to that
of cataract surgery alone.  
Craven, iStent Study Group 2 yr. follow-up2 | 2012 | J Cataract Refract Surg
| PMA | RCT | 98/101 | 2 yr. (199) | 61%/50% (p=0.036) | 53%/44% (p=0.09) |
0.3/0.5 (p=NS) | 8.4/7.5 (p=NS) | Patients with combined single trabecular
micro-bypass stent and cataract surgery had significantly better IOP control
on no medication through 24 months than patients having cataract surgery
alone. Both groups had a similar favorable long-term safety profile.  
Stalmans, (APEX) XEN Study Group4 | 2016 | Abstract presented at European
Glaucoma Society Congress | 510K | Case series | 111 (stent alone) | 1 yr.
(81) | - | 55.6% | 0.7 (p<0.001) c/w preop 2.6 | 8.0 (p<0.001) | The XEN gel
implant offers a minimally invasive and effective surgical alternative that
lowers IOP to the low teens and reduces medication needs in patients with
moderate POAG not controlled with topical hypotensive medications.  
  
*all results are depicted in the format (study group/control group)   
  
According to the 2015 American Academy of Ophthalmology (AAO) POAG Preferred
Practice Pattern (PPP), the "potential benefits of a combined procedure
(cataract extraction with intraocular lens (IOL) implantation and glaucoma
surgery) are protection against the IOP rise that may complicate cataract
surgery alone, the possibility of achieving long-term glaucoma control with a
single operation and elimination of the risk of bleb failure with subsequent
cataract surgery when glaucoma surgery is performed first. Therefore, an
ophthalmologist may reasonably choose to perform a combined surgery because of
these perceived advantages to an individual patient."1  
  
 **Indications and Limitations of Coverage**  
  
The Hydrus Microstent is indicated for use in conjunction with cataract
surgery for the reduction of IOP in adult patients with mild to moderate POAG.
In summary, this A/B Medicare Administrative Contractor (MAC) considers 1
iStent, iStent inject (device capable of delivering 2 individual iStents
per eye) medically reasonable and necessary for the treatment of adults with
mild or moderate OAG and a cataract when the individual is currently being
treated with an ocular hypotensive medication and the procedure is being
performed in conjunction with cataract surgery. In that setting these
procedures offer a reduction in IOP, decreased dependence on glaucoma
medications and an excellent safety profile. However, their role within the
glaucoma treatment algorithm continues to be clarified and differs from the
role of more invasive, external filtration glaucoma surgeries such as
trabeculectomy or external aqueous drainage implants. Therefore, all other
indications are considered not reasonable and necessary at this time.  There
is no additional payment for multiple stents (so-called "dosing"), regardless
of method, since a statistical benefit has not been demonstrated7, especially
in conjunction with cataract surgery.

The XEN45 device received 510K clearance based on having a similar mechanism
(subconjunctival pathway) as "gold standard" filtration procedures
(trabeculectomy and tube shunts), demonstrating "substantial equivalence" in
the pivotal prospective study of patients with refractory glaucoma.9
Equivalency was further established by a relatively large retrospective cohort
study comparing XEN45 with trabeculectomy, finding "no detectable difference
in risk of failure and safety profiles".8 In addition, the American Glaucoma
Society (AGS), the New York State Ophthalmological Society (NYSOS), and
numerous glaucoma experts wrote to support XEN45 as a minimally invasive
method that, "would improve the access of older patients with refractory
glaucoma to surgical care with reduction in post-operative discomfort, shorter
post-operative disability, equivalent efficacy and safety."

This A/B MAC considers 1 XEN45 device per eye medically reasonable and
necessary for the management of refractory glaucoma, defined (based on the
pivotal trial criteria) as prior failure of filtering/cilioablative procedure
and/or uncontrolled IOP (progressive damage and mean diurnal medicated IOP 20
mm Hg) on maximally tolerated medical therapy (i.e., 4 classes of topical
IOP-lowering medications, or fewer in the case of tolerability or efficacy
issues). XEN45 insertion must be performed by an ophthalmologist with
experience with trabeculectomy and bleb management.

Review of Relevant Literature

Technology Assessments:

American Academy of Ophthalmology (AAO): The American Academy of Ophthalmology
(AAO) (Minckler, et al., 2008) conducted a technology assessment on aqueous
shunts for the treatment of Glaucoma. Following a systematic review of the
literature, AAO made the following conclusions:

 Aqueous shunts are comparable to trabeculectomy for IOP control and duration
of benefit.

 Larger explant surface area is related to better IOP control.

 Although primary indication for aqueous shunts is when prior medical or
surgical therapy has failed, they may be used as primary surgical therapy for
selected conditions such as trauma, chemical burns or pemphigoid.

 There is sufficient level I evidence that demonstrates no benefit in using
antifibrotic agents as adjuncts to aqueous shunt procedures.

 There is sufficient level I evidence that demonstrates no benefit of
systemic corticosteroids as adjuncts to aqueous shunt procedures.

 There are insufficient published data to draw any definitive conclusions
about the relative likelihood of early postoperative hypotony with
implantation of valved or nonvalved devices.

The assessment concluded that "based on level I evidence, aqueous shunts offer
a valuable alternative to standard filtering surgery or to cyclodestructive
therapy for many refractory glaucomas. The failure rate is approximately the
same rate for trabeculectomy with adjunctive antifibrotic agents and in
favorable cases shunts may continue to function to control IOP for more than 2
decades."

In a prospective randomized controlled multi-center (29 sites) clinical trial,
Craven et al. (2012) evaluated the long-term safety and effectiveness of a
single trabecular micro-bypass stent with concomitant cataract surgery versus
cataract surgery alone for mild-to-moderate OAG. Eyes with mild-to-moderate
glaucoma with an unmedicated IOP of 22 mmHg or higher and 36 mmHg or lower
were randomly assigned to have cataract surgery with iStent trabecular micro-
bypass stent implantation (stent group) or cataract surgery alone (control
group).  Patients were followed for 24 months postoperatively.  The incidence
of adverse events was low in both groups through 24 months of follow-up. At 24
months, the proportion of patients with an IOP of 21 mmHg or lower without
ocular hypotensive medications was significantly higher in the stent group
than in the control group (p = 0.036).  Overall, the mean IOP was stable
between 12 months and 24 months (17.0 mm Hg  2.8 [SD] and 17.1  2.9 mm Hg,
respectively) in the stent group but increased (17.0  3.1 mm Hg to 17.8  3.3
mm Hg, respectively) in the control group.  Ocular hypotensive medication was
statistically significantly lower in the stent group at 12 months; it was also
lower at 24 months although the difference was no longer statistically
significant.  The authors concluded that patients with combined single
trabecular micro-bypass stent and cataract surgery had significantly better
IOP control on no medication through 24 months than patients having cataract
surgery alone.  Both groups had a similar favorable long-term safety profile.

On June 25, 2012, the FDA approved the iStent Trabecular Micro-Bypass Stent
System, Model GTS100R/L.  This is the first device approved for use in
combination with cataract surgery to reduce IOP in adult patients with mild or
moderate OAG and a cataract who are currently being treated with medication to
reduce IOP. The safety and effectiveness of the iStent Trabecular Micro-
Bypass Stent has not been established as an alternative to the primary
treatment of glaucoma with medications. The effectiveness of this device has
been demonstrated only in patients with mild to moderate OAG who are currently
treated with ocular hypotensive medication and who are undergoing concurrent
cataract surgery for visually significant cataract.

In a retrospective, cohort study, Jea and colleagues (2012) compared the
effect of ab interno trabeculectomy with trabeculectomy.  A total of 115
patients who underwent ab interno trabeculectomy (study group) were compared
with 102 patients who underwent trabeculectomy with intra-operative mitomycin
as an initial surgical procedure (trabeculectomy group).  Inclusion criteria
were OAG, aged greater than or equal to 40 years and uncontrolled on maximally
tolerated medical therapy.  Exclusion criterion was concurrent surgery.
Clinical variables were collected from patient medical records.  Main outcome
measures included IOP and Cox proportional hazard ratio (HR) and Kaplan-Meier
survival analyses with failure defined as IOP greater than 21 mmHg or less
than 20 % reduction below baseline on 2 consecutive follow-up visits after 1
month; IOP less than or equal to 5 mmHg on 2 consecutive follow-up visits
after 1 month; additional glaucoma surgery or loss of light perception vision.
Secondary outcome measures included number of glaucoma medications and
occurrence of complications.  Mean follow-up was 27.3 and 25.5 months for the
study and trabeculectomy groups, respectively.  Intra-ocular pressure
decreased from 28.1 +/- 8.6 mmHg at baseline to 15.9 +/- 4.5 mmHg (43.5 %
reduction) at month 24 in the study group and from 26.3 +/- 10.9 mmHg at
baseline to 10.2 +/- 4.1 mmHg (61.3 % reduction) at month 24 in the
trabeculectomy group.  The success rates at 2 years were 22.4 % and 76.1 % in
the study and trabeculectomy groups, respectively (p < 0.001).  Younger age (p
= 0.037; adjusted HR, 0.98 per year; 95 % CI: 0.97 to 0.99) and lower baseline
IOP (p = 0.016; adjusted HR, 0.96 per 1 mmHg; 95 % CI: 0.92 to 0.99) were
significant risk factors for failure in the multi-variate analysis of the
study group. With the exception of hyphema, the occurrence of postoperative
complications was more frequent in the trabeculectomy group (p < 0.001).  More
additional glaucoma procedures were performed after ab interno trabeculectomy
(43.5 %) than after trabeculectomy (10.8 %, p < 0.001). The authors concluded
that ab interno trabeculectomy has a lower success rate than trabeculectomy.

In 2016, the XEN Glaucoma Treatment System (Allergan, Inc. Aliso Viejo, CA)
was FDA 510(k) approved as a Class II aqueous shunt indicated "for the
management of refractory glaucomas, including cases where previous surgical
treatment has failed, cases of primary open angle glaucoma, and
pseudoexfoliative or pigmentary glaucoma with open angles that are
unresponsive to maximum tolerated medical therapy".

The XEN Glaucoma Treatment System consists of the XEN45 Gel Stent preloaded
into the XEN Injector. The XEN45 Gel Stent is composed of a gelatin derived
from porcine dermis, formed into a tube, and then cross-linked with
glutaraldehyde.

Ab Interno Gel Stent (i.e., XEN Glaucoma Treatment System): Clinical trials
evaluating the safety and effectiveness of the XEN system with
phacoemulsification are lacking. Studies have primarily been in the form of
case series with small patient populations (n=30) with short-term follow-ups
(12 months) (Perez-Torregrosa, et al., 2016).

After receiving FDA approval in July 2016 based on the 2-year safety and
efficacy results of the COMPASS study, Alcon announced a voluntary worldwide
market withdrawal of the CyPass Micro-Stent on August 29, 2018, after 5-year
postoperative data from the COMPASS-XT safety study indicated a statistically
significant corneal endothelial cell loss associated with this device.

Several additional devices are under development/investigation but have not
yet received FDA approval.

Glaucoma is a disease of the eye associated with increased IOP. The majority
(about 90%) of patients with glaucoma have POAG, a chronic condition in which
the IOP is elevated beyond a level compatible with the continued health and
function of the eye, with a gonioscopically open angle and a decreased
facility of outflow.

Traditionally, POAG has been treated with topical ophthalmic medications which
include timolol (a non-specific beta blocker) and latanoprost (a prostaglandin
F2a agonist).  Brimonidine (an alpha agonist) and dorzolamide (a topical
carbonic anhydrase inhibitor) have been employed as second line drugs when
there is suboptimal control of IOP with first line agents. Third-line drugs
may include apraclonidine (an alpha agonist), pilocarpine (a cholinergic
agonist), acetazolamide (an oral carbonic anhydrase inhibitor) and epinephrine
(a non-specific adrenergic agonist). In some patients, the treatment of POAG
may involve multiple topical medications administered at frequent intervals
during the day which is a significant factor in overall medication compliance.

When medications regimens fail to produce a reduction in IOP to a level
significant enough to slow or arrest the progression of optic nerve damage,
surgical interventions may be employed as a next step in the management of
IOP. These interventions include laser trabeculoplasty and/or filtering
procedures such as (a) full-thickness fistulas (e.g., thermal sclerostomy),
(b) partial-thickness fistulas (e.g., trabeculectomy), (3) tubes and setons
(e.g., Molteno implant, Krupin-Denver valve implant, or Ahmed glaucoma
implant) and (4) cyclodestructive procedures (e.g., cyclophotocoagulation or
cyclocryotherapy).

Due to complications with established surgical approaches such as
trabeculectomy, a variety of devices, including aqueous shunts are being
evaluated as alternative surgical treatments for patients with inadequately
controlled glaucoma.

A number of devices known as micro-stents have received FDA approval for
minimally invasive glaucoma procedures. While these devices differ in their
material composition and site of insertion for accomplishing enhanced drainage
of aqueous humor, randomized clinical trials, cost effectiveness and quality
of life studies have shown that these devices may offer a reduction in IOP,
decreased dependence on glaucoma medications and an excellent safety profile.

However, stents and tensioning devices are only able to reduce IOP to the mid-
teens and may be inadequate when very low IOP is needed to reduce glaucoma
damage. Evaluation of outcomes of the use of micro-stents in patients with
mild to moderate OAG currently treated with ocular hypotensive medication is
ongoing.